Microbiology & Immunology - Theses
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ItemDissecting the role of gd T cells in T cell priming for liver stage immunity( 2023-11)Liver resident memory T cells (TRM) are poised for protection against repeat infection and rapidly form a robust defence against tissue-specific insults such as liver stage malaria. A direct correlation between liver stage immunity and gd T cells has been observed both in mice (Zaidi et al. 2017) and in humans (Seder et al. 2013; Ishizuka et al. 2016), but the precise molecular mechanisms by which these gd T cells exert their protective effect are yet to be defined. In mice, intravenous injection with radiation-attenuated sporozoites (RAS) confers sterile protection against challenge with live sporozoites. This protection is mediated by responding antigen-specific CD8+ and CD4+ T cells that migrate to the liver and form resident-memory T cells (TRM). In the absence of gd T cells, protective CD8+ liver TRM are not generated, leaving mice susceptible to reinfection. Using Plasmodium-specific T cells as a readout for effective immunity, we determined that IL-4 is important for the accumulation of CD8+ and CD4+ T cells. By utilising complex in vivo systems including mixed-bone marrow chimeras and adoptive transfer of gd T cells, we revealed that gd T cell-derived IL-4 is crucial for the expansion of antigen-specific CD8+ T cells. In addition, in vivo neutralisation of IL-12 or IFN-g confirmed a partial dependency for these cytokines, despite their traditionally opposing function to IL-4. Given IL-4, IFN-g and IL-12 all have a clear role in CD8+ T cell priming following RAS vaccination, we hypothesised that IL-4 and IFN-g synergise to enhance cDC1 activity. These findings led to our development of a novel model to reconstitute cDC1-deficient mice using CRISPR-edited primary dendritic cells. This model enabled the investigation of the mechanism by which gd T cell derived IL-4 leads to DC activation and therefore effective CD8+ T cell expansion for memory development. Collectively, this project has shown a significant role for IL-4 in the priming of malaria-specific CD8+ T cells and demonstrates a novel pathway for collaboration between gd T cells, cDC1s, and CD8+ T cells, revealing the potential for harnessing gd T cells in vaccination strategies against malaria.
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ItemThe role of T cells in the immunopathology of Helicobacter pylori infections in mice(University of Melbourne, 2007)
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ItemThe role of dendritic cells in CD8+T cell priming after epidermal HSV-1 infection(University of Melbourne, 2006)
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ItemRole of the chemokines CCL17 and CCL22 in bacterial infection and IL-33-induced immune responses( 2023-04)The chemokines CCL17 and CCL22 are primarily expressed by dendritic cells (DC) and macrophages. Both chemokines share the receptor CCR4, which is expressed on DC and macrophages as well as on a variety of different T cell subsets, including Th1 cells, Th2 cells, and regulatory T (Treg) cells. As ligands of CCR4, CCL17 and CCL22 recruit T cells, facilitate the T cell-DC interaction, and sensitise DC for migration. However, CCL17 and CCL22 differ in their distinct signaling pathways and functions, a phenomenon that has been termed biased agonism. CCL17 is involved in the induction and enhancement of numerous allergic and inflammatory diseases. In contrast, CCL22 is rather associated with an immunosuppressive environment. Moreover, CCL17 induces migration and activation of Th1 and Th2 cells as well as sensitising DC migration towards CCR7-ligands, whereas CCL22 facilitates the recruitment of Treg cells. In addition, CCL22 shows higher receptor-binding affinity and induces desensitisation and internalisation of CCR4 more rapidly than CCL17. Although CCL17 and CCL22 were extensively studied in allergic, inflammatory, and autoimmune diseases as well as in the tumor microenvironment, their involvement in infectious diseases has not been well described. Furthermore, IL-33 stimulates the production of CCL17 and CCL22 by DC. In the context of Salmonella infection, IL-33 can be produced by intestinal stroma cells after stimulation with bacterial ligands and IL-33 secretion by pericryptal fibroblasts was shown to be directly protective against the infection. Hence, the aim of this thesis was to elucidate the differential function of CCL17 and CCL22 in the context of Salmonella infection and IL-33-mediated immune responses in organs linked to Salmonella dissemination and beyond. Using a vaccination/challenge Salmonella mouse model, wt, CCL17E/E CCL22-/-, and CCR4-/- mice were investigated for their antigen-specific CD4+ T cell response. Vaccinated CCL17E/E CCL22-/- and CCR4-/- mice were less protected against Salmonella challenge, while vaccinated wt mice survived with 100 %, potentially suggesting an impaired recruitment or positioning of CD4+ T cells and a subsequent defect in clearing the infection. In the context of IL-33-mediated immune responses, CCL22 appeared to play a detrimental role in IL-33-induced adipose tissue fibrosis as adipose tissue morphology exhibited less signs of inflammation, indicated by fibrosis and immune cell infiltration, in CCL22-deficient mice. Moreover, CCL17 and CCL22 were involved in adipose tissue homeostasis in the inguinal white adipose tissue as well as the brown adipose tissue in the case of CCL22. Absence of CCL17, CCL22, and CCR4 caused eosinophilia in the blood, potentially due to an impaired recruitment of eosinophils from the bloodstream into the tissue. Additionally, while IL-33 impaired bone marrow erythropoiesis independently of the CCL17/CCL22/CCR4-axis and thereby caused extramedullary erythropoiesis in the spleen, CCL22 promoted the expansion of basophilic erythroblasts in the spleen. Lastly, comparison of CCL17E/E CCL22-/- and CCR4-/- mice revealed certain phenotypic differences, suggesting the existence of a second receptor for CCL17 and CCL22. Using a chemokine-based receptor staining approach, it was confirmed that CCR4-deficient T cells in the thymus and spleen were still able to bind both chemokines. A putative second receptor, however, was not involved in mediating chemotaxis as CCR4-deficiency abrogated migration of primary T cells from the thymus and of the T cell lymphoma cell line BW5147.3. In conclusion, uncovering both protective and detrimental functions of CCL17 and CCL22 as well as an additional player in the CCL17/CCL22/CCR4-axis opens new aspects to consider in future applications, disease studies and even therapeutically approaches.
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ItemT cell responses to virus infection in the intestinal mucosa( 2022)The intestines are a major reservoir for a range of immune cells, of which CD8+ T cells are key in the elimination of viral infections. The structure of the small and large intestines differs significantly, potentially providing specific tissue niches with different capacities to support immune responses. The structural architecture of the intestines is maintained by a network of stromal cells that contribute to tissue homeostasis and communication with immune cells. Tissue-resident memory T cells (TRM) form following infection and reside in organs such as the gut without recirculating, providing accelerated protective immunity against subsequent infections. In the small intestinal epithelium, most TRM have been characterised by CD103 and CD69 expression in the context of acute infection, where their formation requires the cytokine TGF-beta. However, different infections can modulate TRM formation in different ways, and less is known about the dynamics of T cells in the large intestine. Further, how the stromal cell network influences immune responses in the intestines has not been established. In this thesis, acute and chronic strains of Lymphocytic Choriomeningitis Virus (LCMV) were utilised to characterise T cell and stromal cell populations in the mouse intestine. The antigen-specific CD8+ T cell population underwent a significantly larger contraction in the large versus small intestine after acute LCMV infection. There were low numbers of TRM cells in the large intestine compared to the small intestine, resulting in part from limiting TGF-beta signals in the large intestine. Comparatively, during chronic LCMV infection, LCMV-specific T cells remained in high numbers in both the small and large intestine. The stromal cell network differed significantly between the small and large intestine and was altered during chronic infection. Memory T cells in the large intestine after acute LCMV infection differed phenotypically to those in the small intestine, which may be due to local conversion of circulating memory T cells to TRM. Overall, the work in this thesis has highlighted differential capacities of the small and large intestines to support the formation and maintenance of immune memory after acute viral infection.
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ItemNo Preview AvailableThe molecular and cellular basis of antigen recognition by CD1a-restricted T cells( 2022)In contrast to conventional T cells that recognise peptide antigens presented by MHC molecules, a group of “unconventional” T cells recognise lipid antigens presented by MHC-like CD1 family members, CD1a, CD1b, CD1c and CD1d. Studies suggest that CD1a-restricted T cells comprise a unique subset in human blood that recognise CD1a-lipid complexes and play a unique functional role in skin immunity. While they comprise a decent proportion of T cells compared to CD1d-restricted, natural killer T (NKT) cells, they remain relatively less well-understood. This thesis describes the phenotypic characterisation of CD1a-restricted T cells in human tissues directly ex vivo. Phenotypic analyses and single cell RNA-sequencing of CD1a-restricted T cells revealed that they are distinct from other CD1-restricted T cells. They did not express typical innate-like markers such as CD161, IL-18R, and PLZF, which are expressed by NKT cells, distinguishing them as a unique population of unconventional T cells. This thesis also elucidates how T cell receptors (TCRs) interact with CD1a-lipid complexes. Profiling the TCR repertoire of CD1a-restricted T cells, demonstrated that while diverse, there is a bias towards TCR variable genes that endow optimal TCR configurations to interact with CD1a and lipid antigens. Experiments with CD1a mutant cell lines revealed that individual TCRs bind at various sites across the entire binding cleft of CD1a, which likely increases the diversity of lipid antigens that can be recognised by CD1a-restricted T cells. Indeed, these T cells were observed to recognise numerous lipid antigens including self-lipids and dideoxymycobactin (DDM), a lipid antigen derived from Mycobacterium tuberculosis, with some CD1a-restricted TCRs even displaying cross-reactivity to lipids with distinct chemical structures. Reagents were developed as tools to study lipid-reactive T cells in macaques, especially for non-human primate models of disease. A suite of CD1 tetramers were generated to isolate CD1-restricted T cells in pig-tailed macaques and for preliminary enumeration and phenotypic analysis of CD1-restricted T cell subsets in macaque tissues. Lastly, tetramers were used to investigate CD1a-restricted T cells in human skin. Populations of lipid-reactive T cells and gd-T cells were isolated for phenotypic analysis and TCR sequencing, thus demonstrating that they may play a role in healthy skin. C12-15 alkyl-benzoate, a common oil in dermatological products, was identified as a novel CD1a antigen, suggesting a role for CD1a-restricted T cells in allergic dermatitis. These studies provide insight into the functional properties of CD1a-restricted T cells and their molecular interactions with CD1a-lipids. Collectively, they represent a step forward in characterising CD1a-restricted T cells and provide a greater understanding of their role in the immune system.
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ItemRecognition of Butyrophilin-family Members by gamma-delta T Cells( 2020)Human gamma-delta (gd) T cells can respond rapidly with cytotoxic responses to pathogenic infections and malignant cells. Although they are found at low numbers in peripheral blood, these might expand and constitute up to half of the total circulating T cells after infection. Most systemic gd T cells expressed a recombined heterodimeric T-cell receptor (TCR) with genes of the variable (V) g9 and d2 loci, termed Vg9Vd2 T cells. Opposed to conventional ab T cells that recognise processed peptides on major histocompatibility complex (MHC) class I and II and elicit delayed adaptive responses, gd T cells are innate-like T cells that recognise non-peptidic antigens akin to mucosal-associated invariant T (MAIT) or MHC-like lipid-presenting molecule (CD1)-restricted T cells which recognise vitamin-B derivates or lipids, respectively. The most interesting feature of Vg9Vd2 T cells is that they recognise phosphorylated antigens (aka phosphoantigens) which are essential for life including bacteria and particularly abundant in cancer cells. Little is known how gd T cells recognise phosphoantigens, even though, a few putative ligands have been described. Butyrophilins (BTNs) are a family of transmembrane molecules capable of regulating the immune activity of innate-like gd T cells. They dimerise to constitute complexes, some of which may interact with germline-encoding regions of the gd T cell receptors in murine or human species. For instance, mouse butyrophilin-like (BTNL) molecules shape the Vg7+ gd T-cell compartment in the intestine, while human BTNL counterparts selectively activate Vg4+ gd T cells of the colon. Here, tetrameric gdTCR clonotype probes are used for a genetic screen to identify a previously unknown molecular ligand essential for recognition of phosphorylated antigens by gd T cells. This screen identifies BTN2A1 and subsequent experiments elucidate this protein contacts with the Vg9 domain irrespective of the Vd recombined segment and is essential to confer reactivity to phosphoantigens together with BTN3A1. Thus, BTN2A1 and BTN3A1 constitute a functional complex of which we found both intracellular domains are critically important in maintaining an active conformation. Whereas internal BTN3A1 PRY/SPRY (B30.2) motif senses the antigen, the BTN2A1 intracellular domain appears fundamental to retain association of the complex. Mutagenic alanine screens reveal a dual-ligand binding site for the Vg9Vd2 TCR, where conserved residues of the Vg9 domain bind to BTN2A1 and several residues located at the complementarity-determining regions (CDRs) might react to a putative molecule of the BTN3A family. Thus, this work proposes a phosphoantigen-reactive gd T cells recognise a dual-ligand binding complex where BTN2A1 contacts the Vg9 domain and BTN3A1 is a phosphoantigen sensor molecule that plausibly induces the molecular switch necessary to induce immune responses. Lastly, the influence of tumour infiltrated phosphoantigen-reactive gd T cells in renal carcinogenic tumour patient-derived organoids (PDO) samples is examined and their relevance in healing disease assessed in comparison to previous clinical studies. These results are of vital importance to better understand the potential of gd T cells in prospective medical applications.
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ItemTranscriptional regulation and co-stimulatory signaling in antiviral T cell immunity( 2018)Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer, promoting or repressing gene transcription in mice and human. In this PhD thesis, SATB1 expression was examined in humans across ages and tissues (Chapter 3). The molecular (Chapter 4) and functional (Chapter 5) role of SATB1 was investigated during anti-viral immunity in mice using an influenza (IAV) infection model. Additionally, the effect of CD27-mediated co-stimulation was studied in the context of HIV-1 infection (Chapter 6). SATB1 has pivotal roles during T cell development and maturation, with lineage fate decision in hematopoietic stem cells and gradual changes in SATB1 expression contributing to T cell development in the thymus in mice. In Chapter 3, SATB1 expression was analyzed across lymphocyte compartments from different human tissues and correlated with PD-1 expression in virus-specific CD8+ T cells. SATB1 expression in pediatric and adult donors showed that SATB1 expression was highest in the human thymus with differential expression levels from DN to DP thymocytes and down-regulation of SATB1 in peripheral T cells. Chapter 3 shows that SATB1 expression in the periphery is not static but follows fine-tuned expression dynamics with downregulation from naïve to antigen-specific CD8+ T cells, likely to be antigen- and tissue-dependent. These data led to the hypothesis that fine-tuned SATB1 expression is necessary for maintaining fate-potential in developing and mature, peripheral T cells. Several molecular mechanisms have been identified for gene regulation by SATB1 with wide-range impacts on the overall chromatin landscape. Previous studies in our laboratory showed that SATB1 mRNA levels are high in naïve, but low in effector CD8+ T cells. The impact of SATB1 in repressing transcriptional programs in naïve CD8+ T cells, prior to its downregulation in effector T cells, was addressed in Chapter 4 of this study. ChIP-Sequencing analysis was performed to decipher genomic binding sites of SATB1 in naïve and effector CD8+ T cells. SATB1 ChIP-Seq data demonstrated that SATB1 binding sites were predominately distal to transcriptional start sites, likely to harbor transcriptional enhancer sites, with reduced SATB1 binding sites in effector over naïve CD8+ T cells. To understand the effects of SATB1 on the transcriptional regulation in naïve and IAV-specific CD8+ T cells, SATB1 imposter mice (SATB1imp/imp) were used in this PhD study. In these mice, Satb1 contains a point mutation in the DNA-binding domain encoding position. SATB1 protein expression in SATB1imp/imp mice persists but is dysfunctional with reduced DNA-binding capability. CD8+ T cells from SATB1imp/imp mice showed up-regulation of certain gene profiles, especially at the naïve stage, such as Pdcd1, Ctla4 and Ccl5, characteristic of activated or exhausted T cells. In Chapter 5, an IAV infection model was used, to examine the effects of dysfunctional SATB1 in IAV-specific CD8+ T cell response generation. CD8+ T cell numbers were consistently reduced in SATB1imp/imp mice with significantly reduced IAV-specific CD8+ T cell numbers in lungs on d10 post-infection. SATB1imp/imp CD8+ T cells exhibited an early overexpression of PD-1 from the naïve stage and reduced polyfunctionality within IAV-specific SATB1imp/imp CD8+ T cells. Using a bone marrow chimera approach, in which mice were reconstituted with a mixture of wildtype and SATB1imp/imp-derived lymphocytes, data showed that reduced T cell numbers and PD-1 overexpression are T cell intrinsic in SATB1imp/imp mice. Immunotherapies, including anti-PD-1, anti-CD27 and histone deacetylase inhibitors, are often used in clinical trials to manipulate activation of T cells. In Chapter 6, we used CD27-mediated stimulation to understand the effect on CD4+ T cells with and without HIV-1 infection. CD27 is a co-stimulatory receptor of the TNF-family, expressed on naïve and central memory T cells. Non-permanent stimulation via CD27 leads to increased primary and memory antiviral CD8+ T cell responses in mice. Here, in humans, CD27-mediated stimulation of CD4+ T cells via its ligand CD70 exhibited profound activation potential in vitro, with high CD4+ T cell proliferation and GzmB production. To examine whether this high activation potential could trigger re-activation of viral transcription in latently infected CD4+ T cells, we re-stimulated CD4+ T cells with conventional α-CD28 or CD27-mediated co-stimulation in an in vitro latency model. Unexpectedly, re-stimulation via CD27 of CD4+ T cells led to reduced viral reactivation compared to α-CD28 stimulation of CD4+ T cells. However, similar transcriptional reactivation levels were obtained when CD4+ T cells isolated from HIV+ individuals on ART were re-stimulated with the two protocols. Strikingly, pre-stimulation of CD4+ T cells prior to in vitro HIV-1 infection showed a trend towards reduced HIV-DNA integration and overall infection. This suggests that CD27-mediated stimulation could lead to activation of antiviral mechanisms that reduces CD4+ T cells HIV-1 infection. Overall, this PhD study provides an in-depth understanding of the transcriptional and co-stimulatory regulations of T cell differentiation in response to viral infections. SATB1’s ability to regulate immune checkpoint molecules, such as PD-1 by its DNA-binding capability in antiviral immunity highlights its significance in future PD-1-related cancer and HIV-1 immunotherapy trials used to reverse T cell exhaustion.
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ItemThe role of CD8+ tissue-resident memory T cells in melanoma immune surveillance.( 2018)In addition to its role in protecting the body from infection, the immune system can prevent the development of cancer in a process termed tumour immune surveillance. During this process, immune cells can either recognise and completely eliminate cancerous cells, or can suppress the outgrowth of malignant cells without completely eradicating them. This latter mode of control, designated ‘cancer-immune equilibrium’, can be sustained for extended periods of time in a manner dependent upon adaptive immune cells such as T cells. The vast majority of human cancers are spawned from epithelial tissues. However, long-lived CD8+ circulating memory T (TCIRC) cells such as effector memory T (TEM) cells and central memory T (TCM) cells are typically excluded from epithelial tissue compartments in the absence of robust inflammation. In contrast, CD8+ tissue-resident memory T (TRM) cells are a population of non-migratory immune cells that permanently occupy epithelial tissue sites without recirculating. CD8+ TRM cells provide efficacious protection against peripheral viral and bacterial infections and have recently been identified in a variety of human solid tumours, where they associate with improved disease outcome. However, a direct role for TRM cells in promoting natural immunity to cancer has yet to be demonstrated. In this thesis, we examined the contribution of CD8+ TRM cells to peripheral cancer immune surveillance and the mechanisms through which these cells protect against tumour progression. In order to study the peripherally localised anti-tumour immune response, we developed and characterised an orthotopic epicutaneous (e.c.) model of melanoma in mice that targets tumour growth to the outermost layers of skin. We found that a portion of mice receiving tumour cells e.c. remained free of macroscopic cancer long after inoculation, in a manner that depended upon immune cell mediated control. Spontaneous protection from progressive tumour development was associated with the formation of melanoma-specific CD69+CD103+ CD8+ skin TRM cells, whereas mice genetically deficient in TRM cell formation were highly susceptible to tumour growth. Importantly, tumour-specific skin TRM cells could protect against tumour development independently of TCIRC cells. Closer inspection of macroscopically tumour-free mice revealed that many harboured occult melanoma cells in their skin long after e.c. inoculation. These dormant melanoma cells were retained in the epidermis, where they were dynamically surveyed by tumour-primed CD8+ skin TRM cells. Ablation of skin TRM cells from macroscopically tumour-free mice that were initially protected from tumour development triggered late-stage tumour outgrowth, demonstrating that CD8+ TRM cells can suppress cancer progression by promoting a state of subclinical cancer-immune equilibrium. Further, our findings suggest that the cytokine tumour necrosis factor (TNF) may play a role in the induction and maintenance of this equilibrium state. Overall, we show that CD8+ TRM cells contribute to immune surveillance of peripherally localised cancers by upholding tumour-immune equilibrium. As such, our findings elucidate how cancers arising in epithelial compartments are subject to long-term and ongoing immune suppression. Collectively, our work provides critical insight and the impetus necessary to exploit CD8+ TRM cells as targets of cancer immunotherapies in order to improve solid cancer treatments in patients.
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ItemNo Preview AvailableTracking human CD8+ and γδ T cell receptor repertoire dynamics to understand the impact on immune responses towards influenza viruses( 2018)Seasonal IAV epidemics cause severe morbidity and mortality, resulting in up to 250,000 -600,000 deaths worldwide annually, especially in the young, elderly, immunocompromised, pregnant and those with co-morbidities. Given the segmented nature of the viral genome and a rapid mutational rate, newly-emerging influenza viruses have the potential to cause pandemics. Current seasonal vaccination regimens elicit neutralizing antibodies (nAbs), which require yearly updates to account for the antigenic evolution of influenza viruses. Alternative strategies such as the development of a universal vaccine that can provide broad protection by eliciting immune responses across different strains of influenza viruses are ugently needed. CD8+ T cells recognize internal conserved segments of the viral protein and thus have the potential to provide cross-strain immunity. The efficient immune response of a CD8+ T cell is dictated by the recognition of peptide-MHC complex by its T cell receptor (TCR). However, the response magnitude varies with age and immunogenetics. Similarly, innate γδ T cells are potently activated by stress-induced ligands, independently of classical antigen-presenting molecules and could provide immediate effector function for novel influenza immunotherapies and vaccines. However, much of human γδ T cell biology remains understudied. Therefore, this PhD aimed to determine TCR dynamics of both γδ T cells and influenza-specific CD8+ T cells across different age groups, anatomical locations and influenza infection. Aim 1 explored the diversity of the human γδ T cell TCR repertoire and how γδ T cells are actived by influenza viruses. We implemented a single-cell RT-PCR for paired analysis of the TCRγ and TCRδ chains and developed an in vitro infection model of influenza-infected lung epithelial cells co-cultured with peripheral blood mononuclear cells (PBMCs). We performed a thorough repertoire analysis of ex vivo γδ T cells from cord blood, young adult, elderly adult and human tissues (spleen, lung and lymph node). Our analyses found diverse and private γδ T cells in cord blood and spleen, while those in young adults and lungs were highly focused towards invariant γ9δ2 TCRs. Elderly adult γδ T cells displayed expansion of private or the invariant γ9δ2 clonotypes. Using the in vitro infection model of influenza, we next investigated γδ TCRs which produced IFNγ during an in vitro influenza infection and PBMC co-culture. Our results demonstrated that the majority of responding γδ T cells harbored γ9δ2 TCRs. We observed heterogeneity in the influenza response between cord blood, young adult and elderly adults. γδ T cells within cord blood and the elderly adults had minimal IFN- production in the absence of γ9δ2 TCRs. Thus, this study provided an understanding on how γδ T cells contribute to immune protection during influenza infection and which TCRs are important to elicit across all age groups vulnerable to influenza virus infection. In Aim 2 and 3, we tracked the repertoire dynamics of influenza specific CD8+ T cells across age groups and tissue locations. Since HLA-A*02:01-restricted M158-66 viral peptide has high sequence conservation and elicits immunodominant CD8+ responses, we focused our analyses on HLA-A*02:01-M158+CD8+ TCRs. A robust response elicited by HLA-A*02:01-M158+CD8+ TCRs is governed by the presence of the public TCR signature, TRBV19/TRAV27 (CDR3 motif “GGSQGNL”/“SIRSYEQ”). Our study demonstrated the loss of this public TCR and presence of large private clonotypes in the HLA-A*02:01-M158+CD8+ TCRs isolated from the elderly donors, as compared to young adults who maintained high frequencies of public TCRs. Our study showed, for the first time, HLA-A*02:01-M158+CD8+ T cells were present in human tissues (spleen, lung and lymph nodes) obtained from young adults. Furthermore, lung tissue-resident HLA-A*02:01-M158+CD8+ T cells and those isolated from spleen and lymph nodes displayed a prominent presence of public TCRs. Overall, we showed a loss of public TCRs with aging and we speculate that this is a mechanism underlying reduced immune responsiveness during influenza infection with aging. Moreover, the presence of public TCRs in distal tissues could provide a reservoir to replenish “optimum” TCRs at the site of infection. The magnitude of antigen-specific CD8+ T cells can be influenced by the different Human Leukocyte Antigens (HLAs) expressed by an individual, thus contributing to the phenomenon of CD8+ T cell immunodominance hierarchy. Using the known highly conserved immunodominant epitopes restricted by 6 HLAs that have broad coverage towards influenza viruses across different ethnicities, we compared the response magnitude of these epitope-specific CD8+ T cells to that of HLA-A*02:01-M158+CD8+ T cells. We showed that individuals co-expressing HLA-B*27:05 and HLA-A*02:01 had higher magnitude of B*27:05-NP383+CD8+ T cell responses compared to that of A*02:01-M158+CD8+ T cells. Our findings showed that B27/NP383+CD8+ T cells had higher functional capacity as compared to A02/M158+CD8+ T cells. Moreover, TCRs of A02/M158+CD8+ T cells from heterozygous donors showed a reduction or complete loss of the public TCR present in A*02:01+B*27:05- individuals. This suggested that the reduction in the observed magnitude of response was partly attributed to changes within the A02/M158 TCR repertiore. Overall, this PhD contributes to our understanding of innate and adaptive T cell compartments during influenza virus infection. It provides evidence that influenza-specifc γδ and CD8+ T cell immune responses are affected by age, HLA genotype and alterations in the TCR repertoire. These findings form an important foundation for future research developing universal vaccines against influenza viruses and immunotherapies against viral infections or cancer.