Effector-Memory T Cells Develop in Islets and Report Islet Pathology in Type 1 Diabetes

Chee, Jonathan; Ko, Hyun Ja; Skowera, Ania; Jhala, Gaurang; Catterall, Tara; Graham, Kerr; Sutherland, Robyn M.; Thomas, Helen E.; Lew, Andrew M.; Peakman, Mark; Kay, Thomas W. H.; Krishnamurthy, Balachander

doi:10.4049/jimmunol.1302100

Cited by 49 publications

(58 citation statements)

References 33 publications

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“…The latter point has been debated: using double-retrogenic mice, in which specificity is controlled, Lennon et al (11) showed that only antigen-specific cells accumulate in the insulitis after transfer into NOD.scid mice, and only T cells specific for β-cell antigens localized to islets in the first hours after transfer (12,13) in other studies. However, antigen-specific cells identified by tetramer staining are only modestly enriched in the pancreas relative to irrelevant lymphoid organs, and there is still ample participation by other cells (14,15). Polyclonal populations, unlikely to be antigen specific, accompanied cells from specific clones injected into NOD mice (16).…”

mentioning

confidence: 99%

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Magnuson

Thurber

Köhler

et al. 2015

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

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Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing β-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b + c + myeloid cells. Both naïve-and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3 + regulatory T cells circulated less than their conventional CD4 + counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.Treg | cell tracer | reporter T ype-1 diabetes (T1D) is an organ-specific autoimmune disease initiated by a breakdown in T lymphocyte tolerance to islet-cell antigens; it comprises two stages: an occult phase of pancreatic inflammation, which reduces the number and function of insulin-producing β-cells and eventually provokes sufficient damage to result in the overt phase of diabetes, when insulin production is insufficient for proper glucose homeostasis. The genetics of T1D in mice and humans point primarily to a dysfunction of CD4 + T cells, because class II genes of the MHC, and several other loci that modify T-cell activation and regulation, are linked to T1D susceptibility (1).In nonobese diabetic (NOD) mice and other animal models (2), this initial inflammatory phase takes the form of insulitis, wherein a mixed population of leukocytes invades the islets of Langerhans. Insulitis starts around 3-4 wk of age and amplifies progressively until the onset of clinically overt diabetes (predominantly between 14 and 25 wk of age); it involves a wide array of cell types-T and B lymphocytes as well as myeloid cells-macrophages and dendritic cells (3), which can take on the organization of typical tertiary lymphoid structures (4). Importantly, insulitis variably affects different islets in a given animal, heavily infiltrated islets coexisting with fully intact and functional ones, even in advanced prediabetic mice.Inflammation in islets of human patients has been harder to evaluate, because access to material is obviously more difficult...

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mentioning

confidence: 99%

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Magnuson

Thurber

Köhler

et al. 2015

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

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“…In the NOD model, there was an increase of islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-specific CD8 + T EM cells in the peripheral lymphoid tissue (spleen and peripheral lymph nodes) after 10 weeks of age, which correlated with severity of insulitis in these mice (48). In our CTLA4RNAi/B6.H2 g7 model of juvenile-onset T1D that harbors a natural polyclonal T-cell repertoire as in the NOD model, we did not detect substantial impact of CD8 + memory T cells on the early onset of autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 99%

Opposing Effects of CTLA4 Insufficiency on Regulatory versus Conventional T Cells in Autoimmunity Converge on Effector Memory in Target Tissue

Devarajan

Miska

Lui

et al. 2014

The Journal of Immunology

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Quantitative variations in CTLA4 expression, due to genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T (Treg) cells, but also required for intrinsic control of conventional T (Tconv) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg cell function both in vivo and in vitro. It led to an increase in Treg memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNAi or antibody blockade promoted effector memory (TEM) formation in the Tconv compartment. The CD4+ TEM cells, including those within target tissue, produced IL17 or IFNγ. Blocking IL7 signaling reduced the Th17 autoimmune compartment, but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both Tconv and Treg lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, while the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T-cell immunity while suppressing tissue damage.

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“…These populations increased in frequency as the mice aged and were able to migrate into the islets. IGRP specific CD8 þ T cells could mediate target cell lysis and developed a memory phenotype with age [57,61]. Insulin specific CD4 þ T cells from NOD mice were able to produce IFNg upon stimulation [58].…”

Section: Phenotyping Islet-specific T Cells In Nod Mice Reveals Multimentioning

confidence: 98%