Chapter 4 CD8+ T Cells in Type 1 Diabetes

Tsai, Sue; Shameli, Afshin; Santamaría, Pere

doi:10.1016/s0065-2776(08)00804-3

Cited by 115 publications

(86 citation statements)

References 209 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…are present at very low precursor frequencies in the islets of prediabetic mice (20,21,28), such as insulin-B 15-23 -reactive CD8 + T cells (29) (Fig. 1G).…”

Section: Resultsmentioning

confidence: 99%

“…Notwithstanding that in vitro-activated bystander T cell clones can transiently comigrate with their cognate counterparts into noninflamed tissue in adoptive T cell transfer experiments and that tissue-specific expression of cytokine and/or chemokine transgenes in normal tissues can trigger bystander T cell inflammation, these models do not faithfully mimic the events that take place in spontaneous autoimmune inflammation. Specifically, it is unclear that bystander T cell specificities can effectively compete with their cognate polyclonal counterparts, recognizing pMHC in situ, for occupation of the inflammatory space.Type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is a chronic autoimmune disease that results from inflammation of pancreatic islets and destruction of pancreatic β cells by T cells targeting numerous β cell autoantigens (20,21). A significant fraction of the islet-associated CD8 + T cells in NOD mice recognize the mimotope NRP-V7 in the context of the MHC molecule K d (22)(23)(24)(25).…”

mentioning

confidence: 99%

“…Type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is a chronic autoimmune disease that results from inflammation of pancreatic islets and destruction of pancreatic β cells by T cells targeting numerous β cell autoantigens (20,21). A significant fraction of the islet-associated CD8 + T cells in NOD mice recognize the mimotope NRP-V7 in the context of the MHC molecule K d (22)(23)(24)(25).…”

mentioning

confidence: 99%

See 2 more Smart Citations

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

Wang

Tsai

Shameli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8 + T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [206][207][208][209][210][211][212][213][214] in gene-targeted nonobese diabetic (NOD) mice expressing a T cell "invisible" IGRP 206-214 sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP 206-214 -reactive CD8 + T cells. Conversely, IGRP 206-214 -reactive, but not nonautoreactive CD8 + T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8 + T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8 + T cells contained in extralymphoid autoimmune lesions are largely autoreactive.diabetes | lymphocyte | islet-specific glucose-6-phosphatase catalytic subunit-related protein | islet inflammation | lymphocyte recruitment R ecognition of cognate peptide-major histocompatibility complexes (pMHC) on the surface of dendritic cells (DC) by naive T lymphocytes in lymph nodes draining a site of infection or autoimmune inflammation elicits the lymphocytes' activation, proliferation, and differentiation into cytolytic effectors. Upon activation, lymphocytes also acquire the ability to survey nonlymphoid tissues for presence of their cognate target antigens, with a preference for inflamed tissues as well as tissues drained by the lymph nodes where activation took place (1-3). Studies in a number of infection and autoimmune disease models have suggested that recruitment of T lymphocytes into a site of extralymphoid inflammation does not require local expression of cognate (foreign or self) pMHC on tissue cells or tissue-associated antigen-presenting cells (APCs) (4-7). Accordingly, it is generally thought that non-antigen-specific inflammatory cues such as cytokines and chemokines emanating from the local microenvironment can recruit noncognate (i.e., bystander) T cells to a site of foreign or self antigen-triggered tissue inflammation (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Notwithstanding that in vitro-activated bystander T cell clones can transiently comigrate with their cognate counterparts into noninflamed tissue in adoptive T cell transfer experiments and that tissue-specific expression of cytokine and/or chemokine transgenes in normal tissues can trigger bystander T cell inflammation, these models do not faithfully mimic the events that tak...

show abstract

“…are present at very low precursor frequencies in the islets of prediabetic mice (20,21,28), such as insulin-B 15-23 -reactive CD8 + T cells (29) (Fig. 1G).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

Wang

Tsai

Shameli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although CD8 1 T cells are primarily considered to play a role as effectors of target cell killing, they may also be important in disease establishment [6,7]. CD4 1 T cells, on the other hand, contribute to autoimmune and inflammatory diseases in a wide variety of ways.…”

Section: Introductionmentioning

confidence: 99%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

View full text Add to dashboard Cite

CD4 1 T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4 1 memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitrogenerated CD4 1 memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4 1 T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.Key words: CD4 1 T cells . DC . Tolerance See accompanying Commentary by Kurts IntroductionNegative selection and peripheral tolerance mechanisms jointly serve to limit the development of autoaggressive self-reactive T-cell responses. However, in autoimmune-prone individuals these control mechanisms can fail and autoimmune disease ensues. As autoimmune diseases progress, intra-and intermolecular determinant spreading occurs [1] and populations of effector and memory T cells become established. Therefore, unlike strategies directed at preventing the development of autoimmune disease, where induction of tolerance in naïve T cells may be all that is required, therapies aimed at terminating ongoing autoimmune disease must be capable of inactivating established populations of memory or activated effector T cells.Although naïve T cells are highly dependent on the presence or absence of costimulatory signals to determine the outcome of activation, costimulation appears to play little role in controlling the responses of memory and effector T cells [2,3] and these cells are considered costimulation independent. Because of this, in contrast to naïve T cells which are readily deleted or inactivated in the absence of costimulation memory T cells are widely regarded as potentially resistant to tolerance induction. If this were indeed the case, then effector and memory T cells represent a significant hurdle to therapeutic strategies aimed at treating autoimmune diseases. However, we have recently shown that memory and effector CD8 1 T cells are susceptible to tolerance induction when cognate antigen is expressed in DC and other APC types [4]. 2016The relative roles of CD4 1 and CD8 1 T cells in disease progression differ depending on the autoimmune disease bu...

show abstract

“…In human T1D, islet-specific CTLs have been identified and histology shows CTLs in the islets, whereas in the non-obese diabetic (NOD) mouse, CTLs are implicated in the initial stages as well as in progression of disease. [1][2][3][4][5][6] Selective immunotargeting of diabetogenic CTLs is therefore a promising avenue for immunotherapy of T1D.…”

Section: Introductionmentioning

confidence: 99%

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

et al. 2017

View full text Add to dashboard Cite

Chapter 4 CD8+ T Cells in Type 1 Diabetes

Cited by 115 publications

References 209 publications

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

Contact Info

Product

Resources

About

Chapter 4 CD8+ T Cells in Type 1 Diabetes

Cited by 115 publications

References 209 publications

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+T cell inflammation

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+T cell inflammation

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

Contact Info

Product

Resources

About

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺T cell inflammation

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses