Biochemistry and Pharmacology - Research Publications
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ItemRapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold(AMER ASSOC IMMUNOLOGISTS, 2013-10-01)Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8(+) dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.
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ItemInflammation Conditions Mature Dendritic Cells To Retain the Capacity To Present New Antigens but with Altered Cytokine Secretion Function(AMER ASSOC IMMUNOLOGISTS, 2014-10-15)Dendritic cells (DCs) are directly activated by pathogen-associated molecular patterns (PAMPs) and undergo maturation. Mature DCs express high levels of MHC class II molecules ("signal 1"), upregulate T cell costimulatory receptors ("signal 2"), and secrete "signal 3" cytokines (e.g., IL-12). Mature DCs efficiently present Ags linked to the activating PAMP and prime naive T cells. However, mature DCs downregulate MHC II synthesis, which prevents them from presenting newly encountered Ags. DCs can also be indirectly activated by inflammatory mediators released during infection (e.g., IFN). Indirectly activated DCs mature but do not present pathogen Ags (as they have not encountered the pathogen) and do not provide signal 3. Therefore, although they are probably generated in large numbers upon infection or vaccination, indirectly activated DCs are considered to play little or no role in T cell immunity. In this article, we show that indirectly activated DCs retain their capacity to present Ags encountered after maturation in vivo. They can also respond to PAMPs, but the previous encounter of inflammatory signals alters their cytokine (signal 3) secretion pattern. This implies that the immune response elicited by a PAMP is more complex than predicted by the examination of the immunogenic features of directly activated DCs, and that underlying inflammatory processes can skew the immune response against pathogens. Our observations have important implications for the design of vaccines and for the understanding of the interactions between simultaneous infections, or of infection in the context of ongoing sterile inflammation.
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ItemThe inflammatory cytokine, GM-CSF, alters the developmental outcome of murine dendritic cells(WILEY, 2012-11)Fms-like tyrosine kinase 3 ligand (Flt3L) is a major cytokine that drives development of dendritic cells (DCs) under steady state, whereas GM-CSF becomes a prominent influence on differentiation during inflammation. The influence GM-CSF exerts on Flt3L-induced DC development has not been thoroughly examined. Here, we report that GM-CSF alters Flt3L-induced DC development. When BM cells were cultured with both Flt3L and GM-CSF, few CD8⁺ equivalent DCs or plasmacytoid DCs developed compared to cultures supplemented with Flt3L alone. The disappearance of these two cell subsets in GM-CSF + Flt3L culture was not a result of simple inhibition of their development, but a diversion of the original differentiation trajectory to form a new cell population. As a consequence, both DC progeny and their functions were altered. The effect of GM-CSF on DC subset development was confirmed in vivo. First, the CD8⁺ DC numbers were increased under GM-CSF deficiency (when either GM-CSF or its receptor was ablated). Second, this population was decreased under GM-CSF hyperexpression (by transgenesis or by Listeria infection). Our finding that GM-CSF dominantly changes the regulation of DC development in vitro and in vivo has important implications for inflammatory diseases or GM-CSF therapy.