Microbiology & Immunology - Research Publications
Permanent URI for this collection
Search Results
1 - 9 of 9
-
ItemInduction of a CD8(+) cytotoxic T lymphocyte response by cross-priming requires cognate CD4(+) T cell help(ROCKEFELLER UNIV PRESS, 1997-07-07)Class I-restricted presentation is usually associated with cytoplasmic degradation of cellular proteins and is often considered inaccessible to exogenous antigens. Nonetheless, certain exogenous elements can gain entry into this so-called endogenous pathway by a mechanism termed cross-presentation. This is known to be effective for class I-restricted cytotoxic T lymphocyte (CTL) cross-priming directed against a variety of exogenous tumor, viral, and minor transplantation antigens. The related effect of cross-tolerance can also effectively eliminate responses to selected self components. In both cases, this presentation appears to require the active involvement of a bone marrow-derived antigen presenting cell (APC). Here, we show that CTL induction by cross-priming with cell-associated ovalbumin requires the active involvement of CD4+ helper T cells. Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC. Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.
-
ItemCD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity(ROCKEFELLER UNIV PRESS, 1997-12-15)Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I-restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4+ T cell help on this process. Small numbers of autoreactive OVA-specific CD8+ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic beta cells. Coinjection of OVA-specific CD4+ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.
-
ItemCross-tolerance: A pathway for inducing tolerance to peripheral tissue antigens(ROCKEFELLER UNIV PRESS, 1998-05-18)
-
ItemB cells directly tolerize CD8+ T cells(ROCKEFELLER UNIV PRESS, 1998-12-07)This report investigates the response of CD8(+) T cells to antigens presented by B cells. When C57BL/6 mice were injected with syngeneic B cells coated with the Kb-restricted ovalbumin (OVA) determinant OVA257-264, OVA-specific cytotoxic T lymphocyte (CTL) tolerance was observed. To investigate the mechanism of tolerance induction, in vitro-activated CD8(+) T cells from the Kb-restricted, OVA-specific T cell receptor transgenic line OT-I (OT-I cells) were cultured for 15 h with antigen-bearing B cells, and their survival was determined. Antigen recognition led to the killing of the B cells and, surprisingly, to the death of a large proportion of the OT-I CTLs. T cell death involved Fas (CD95), since OT-I cells deficient in CD95 molecules showed preferential survival after recognition of antigen on B cells. To investigate the tolerance mechanism in vivo, naive OT-I T cells were adoptively transferred into normal mice, and these mice were coinjected with antigen-bearing B cells. In this case, OT-I cells proliferated transiently and were then lost from the secondary lymphoid compartment. These data provide the first demonstration that B cells can directly tolerize CD8(+) T cells, and suggest that this occurs via CD95-mediated, activation-induced deletion.
-
ItemClass I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells(ROCKEFELLER UNIV PRESS, 1997-07-21)In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.
-
ItemConstitutive class I-restricted exogenous presentation of self antigens in vivo(ROCKEFELLER UNIV PRESS, 1996-09-01)Ovalbumin (OVA)-specific CD8+ T cells from the T cell receptor-transgenic line OT-I (OT-I cells) were injected into unirradiated transgenic RIP-mOVA mice, which express a membrane-bound form of OVA (mOVA) in the pancreatic islet beta cells and the renal proximal tubular cells. OT-I cells accumulated in the draining lymph nodes (LN) of the kidneys and pancreas and in no other LN. They displayed an activated phenotype and a proportion entered cell cycle. Unilateral nephrectomy 7-13 d before inoculation of OT-I cells into RIP-mOVA mice allowed the injected T cells to home only to the regional LN of the remaining kidney (and pancreas), but when the operation was performed 4 h before injecting the T cells, homing to the LN of the excised kidney was evident. When the bone marrow of RIP-mOVA mice was replaced with one of a major histocompatibility haplotype incapable of presenting OVA to OT-I cells, no homing or activation was detectable. Therefore, OT-I cells were activated by OVA presented by short-lived antigen-presenting cells of bone marrow origin present in the draining LN of OVA-expressing tissue. These results provide the first evidence that tissue-associated "self" antigens can be presented in the context of class I via an exogenous processing pathway. This offers a constitutive mechanism whereby T cells can be primed to antigens that are present in nonlymphoid tissues, which are not normally surveyed by recirculating naive T cells.
-
ItemThe peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1)(ROCKEFELLER UNIV PRESS, 1998-07-20)Recently, we demonstrated that major histocompatibility complex class I-restricted cross-presentation of exogenous self-antigens can induce peripheral T cell tolerance by deletion of autoreactive CD8+ T cells. In these studies, naive ovalbumin (OVA)-specific CD8+ T cells from the transgenic line OT-I were injected into transgenic mice expressing membrane-bound OVA (mOVA) under the control of the rat insulin promoter (RIP) in pancreatic islets, kidney proximal tubules, and the thymus. Cross-presentation of tissue-derived OVA in the renal and pancreatic lymph nodes resulted in activation, proliferation, and then the deletion of OT-I cells. In this report, we investigated the molecular mechanisms underlying this form of T cell deletion. OT-I mice were crossed to tumor necrosis factor receptor 2 (TNFR2) knockout mice and to CD95 (Fas, Apo-1) deficient mutant lpr mice. Wild-type and TNFR2-deficient OT-I cells were activated and then deleted when transferred into RIP-mOVA mice, whereas CD95-deficient OT-I cells were not susceptible to deletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cells in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This study represents the first evidence that CD95 is involved in the deletion of autoreactive CD8+ T cells in the whole animal.
-
ItemMajor histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction(ROCKEFELLER UNIV PRESS, 1998-07-20)Naive T cells recirculate mainly within the secondary lymphoid compartment, but once activated they can enter peripheral tissues and perform effector functions. To activate naive T cells, foreign antigens must traffic from the site of infection to the draining lymph nodes, where they can be presented by professional antigen presenting cells. For major histocompatibility complex class I-restricted presentation to CD8+ T cells, this can occur via the cross-presentation pathway. Here, we investigated the conditions allowing antigen access to this pathway. We show that the level of antigen expressed by peripheral tissues must be relatively high to facilitate cross-presentation to naive CD8+ T cells. Below this level, peripheral antigens did not stimulate by cross-presentation and were ignored by naive CD8+ T cells, although they could sensitize tissue cells for destruction by activated cytotoxic T lymphocytes (CTLs). Interestingly, CTL-mediated tissue destruction facilitated cross-presentation of low dose antigens for activation of naive CD8+ T cells. This represents the first in vivo evidence that cellular destruction can enhance access of exogenous antigens to the cross-presentation pathway. These data indicate that the cross-presentation pathway focuses on high dose antigens and those released during tissue destruction.
-
ItemIntermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes.(Rockefeller University Press, 1995-05-01)The differentiation potential of putative intermediates between CD4+8+ thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4+8+ thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II-deficient mice, mice transgenic for an alpha/beta T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4+8intTCRint-derived progeny were found to be CD4-8+TCRhi cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8+TCRint thymocytes produced CD4-8+TCRhi cells but no significant proportion of CD4+8-TCRhi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8+ versus CD4+8- T cells.