Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)

Simpson, Tyler R.; Quezada, Sergio A.; Allison, James P.

doi:10.1016/j.coi.2010.01.001

Cited by 197 publications

(184 citation statements)

References 58 publications

(87 reference statements)

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“…ICOS and ICOSL gene targeting studies have revealed a key role of ICOS-ICOSL interactions at multiple stages of T cell-dependent primary Ab responses (25,26). These include GC formation, Ig class switching, and the development as well as acquisition of effector functions by Th cell subsets, such as T follicular helper (Tfh) cells (25,26,42,43).…”

Section: Discussionmentioning

confidence: 99%

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

Marczynska

Ozga

Włodarczyk

et al. 2014

The Journal of Immunology

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Immune cells regulate cell surface receptor expression during their maturation, activation, and motility. Although many of these receptors are regulated largely at the level of expression, protease-mediated ectodomain shedding represents an alternative means of refashioning the surface of immune cells. Shedding is largely attributed to a family of a disintegrin and metalloprotease domain (ADAM) metalloproteases, including ADAM17. Although ADAM17 is well known to contribute to the innate immune response, mainly by releasing TNF-α, much less is known about whether/how this metalloprotease regulates adaptive immunity. To determine whether ADAM17 contributes to regulating adaptive immune responses, we took advantage of ADAM17 hypomorphic (ADAM17ex/ex) mice, in which ADAM17 expression is reduced by 90–95% compared with wild-type littermates. In this study, we show that that ADAM17 deficiency results in spleen and lymph node enlargement, as well as increased levels of Ag-specific class-switched Ig production following immunization with OVA together with anti-CD40 mAbs and polyinosinic-polycytidylic acid. Moreover, we demonstrate that the costimulatory ligand ICOS ligand (ICOSL) is selectively downregulated on the surface of B cells in an ADAM17-specific manner, although it is not proteolitically processed by recombinant ADAM17 in vitro. Finally, we show that higher cell surface levels of ICOSL in ADAM17ex/ex mice may contribute to the development of excessive Ab responses. Therefore, our data suggest a functional link between ADAM17 and ICOSL in controlling adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

Marczynska

Ozga

Włodarczyk

et al. 2014

The Journal of Immunology

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“…34 More exciting are novel monoclonal antibodies, currently being evaluated in autoimmune diseases, graft tolerance or antitumor immunity, which specifically target molecules expressed on AITL tumor cells, such as PD1 35 and ICOS. 36 Our biological study focusing on B cells and EBV, which was conducted in parallel to the clinical trial in order to correlate a potential benefit of rituximab with biological features at diagnosis, provided original data regarding clinical practice and pathophysiological hypotheses. We found circulating tumor cells in 54% of patients.…”

Section: Discussionmentioning

confidence: 99%

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundIn angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20 + large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. Design and MethodsTwenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. ResultsA complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median followup of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/mg DNA) was associated with shorter progression-free survival (P=0.06). ConclusionsWe report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20 + B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted. (This trial was registered at www.clinicaltrials.gov as NCT00169156.)

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“…Unlike CD28, ICOS does not impact Grb2 and NF-κB signaling, but it does activate the PI3k-Akt pathway and can deliver positive costimulatory signals. More specifically, ICOS promotes T-cell differentiation toward B-cell help, favoring expression of IL4 and the T "follicular helper" phenotype (10).…”

mentioning

confidence: 99%

Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4 ⁺ T cells

Wakamatsu

Mathis

Benoist

2012

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

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Costimulatory molecules of the CD28 family on T lymphocytes integrate cues from innate immune system sensors and modulate activation responses in conventional CD4 + T cells (Tconv) and their FoxP3 + regulatory counterparts (Treg). To better understand how costimulatory and coinhibitory signals might be integrated, we profiled the changes in gene expression elicited in the hours and days after engagement of Treg and Tconv by anti-CD3 and either anti-CD28, -CTLA4, -ICOS, -PD1, -BLA, or -CD80. In Tconv, a shared “main response” was induced by CD28, ICOS, and, surprisingly, BTLA and CD80, with very limited CD28-specific (primarily Il2 ) or ICOS-specific elements (including Th1 and Th2 but not the follicular T signature). CTLA4 and PD1 had a very subtle impact in this system, similarly inhibiting the response to anti-CD3. Treg responded to the same costimulatory hierarchy and to the same extent as Tconv, but inducing different clusters of genes. In this reductionist system, costimulatory or coinhibitory engagement mainly elicits generic responses, suggesting that the variability of their effects in vivo result from temporal or anatomical differences in their engagement, rather than from inherently different wiring.

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Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)

Cited by 197 publications

References 58 publications

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4 ⁺ T cells

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Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)

Cited by 197 publications

References 58 publications

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4 + T cells

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Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4 ⁺ T cells