ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells

Burmeister, Yvonne; Lischke, Timo; Dahler, Anja Christina; Mages, Hans W.; Lam, Kong-Peng; Coyle, Anthony J.; Kroczek, Richard A.; Hutloff, Andreas

doi:10.4049/jimmunol.180.2.774

Cited by 236 publications

(265 citation statements)

References 39 publications

(41 reference statements)

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“…Finally, costimulation with DLL4-Fc elevated both mRNA and cell surface levels of ICOS (inducible T-cell costimulator) (Fig. 4 E and F), a receptor implicated in control of CD4 + effector cell survival (32). In summary, Notch activates a broad gene expression program to protect activated CD4 + T cells from cell death.…”

Section: Resultsmentioning

confidence: 99%

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

Helbig¹,

Gentek²,

Backer³

et al. 2012

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

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Generation of effective immune responses requires expansion of rare antigen-specific CD4 + T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4 + T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4 + T cells. Instead, Notch protects activated CD4 + T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4 + T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4 + T-cell responses by promoting cellular longevity.

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Section: Resultsmentioning

confidence: 99%

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

Helbig¹,

Gentek²,

Backer³

et al. 2012

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

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“…46 On the contrary, these molecules as well as ICOS also facilitate the expansion of T reg cells. 36,45,47 B cells of aged BWF1 mice, however, did not show significant expression of ligands for these co-stimulatory molecules (data not shown). This observation implies that reversal of the suppression, if any, might take place through the other pathway(s).…”

Section: Discussionmentioning

confidence: 99%

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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Foxp3 ؉ CD4 ؉ regulatory T (T reg ) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T reg cells in (NZB ؋ NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T reg cells trafficked to target organs because cells were present in the kidney and lung. T reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of costimulatory molecules were also markedly enhanced in the T reg cells of aged BWF1 mice. Furthermore, T reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by a massive production of autoantibodies against various nuclear antigens. The deposit of immune complexes in the target organs, ie, skin, kidney, lung, joints, and central nervous system, is thought to cause fatal dysfunction of the body system. (NZB ϫ NZW) F1 (BWF1) is a mouse strain that has been widely used as a model for SLE since the 1960s. These mice spontaneously develop severe autoimmune disease highly resembling human SLE in terms of serological and hematological abnormalities, and severe nephritis accompanying massive production of antinuclear antibodies. 1 Reconstitution of SCID (severe combined immunodeficiency) mice with cultured pre-B cells of BWF1 mice recapitulates many symptoms of the disease of BWF1 mice. Cultured pre-B cells alone, however, are not sufficient to fully reproduce the disease. 2 These data suggest that cellular subset(s) in addition to B cells are necessary for the development of the lupus-like syndrome of BWF1 mice, although abnormalities of the immune system predominantly lie within B cells. One of the possible candidates is CD4 ϩ T cells, because depletion of CD4 ϩ T cells with anti-CD4 antibody from 5 months old, slightly before the disease onset, prevents the development of the disease. 3,4 CD4 ϩ T cells are, therefore, also required for the development of the disease in BWF1 mice, possibly by providing help for the production of high-affinity autoantibodies.Studies in this decade have clearly shown the key roles of naturally occurring regulatory T (T reg ) cells in the maintenance of dominant self tolerance of the immune system. 5 T reg cells in normal mi...

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“…30 It has been shown that ICOS critically controls the pool size of both effector memory and regulatory T cells. 31 In our study, comprising the global cohort of 77 patients, no significant changes in the frequency of ICOS C CD4 C T and CD8 C T cells from baseline to week 6 were observed (Fig. S2).…”

Section: Ipilimumab Induces Early Immunological Changes Of T Cell Submentioning

confidence: 93%

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

et al. 2016

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Purpose: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. Experimental design: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. Results: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 £ 10 9 /L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes C and Ki-67 C T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. Conclusion: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.

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ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells

Cited by 236 publications

References 39 publications

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

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