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Regulation of CD4? and CD8? effector responses by Sprouty-1.

ABSTRACT: TCR-induced NF-AT activation leads to the expression of both activating and inhibitory proteins. Previously, we had identified Egr-2 and Egr-3 as NF-AT-induced transcription factors which promote the inhibition of T cell activation. In this report we identify Sprouty1 as a downstream target of Egr-3. CD4? T cells lacking Spry1 demonstrate enhanced proliferation and cytokine production. Likewise, Spry1(Flox/Flox) Lck Cre CD8? T cells display increased cytolytic activity. Mechanistically, Spry1 acts at the level of PLC-? promoting the inhibition of both Ca?? induced NF-AT activation and MAP-kinase induced AP-1 activation while sparing NF-?B signaling. In vivo, mice in which Spry1 is selectively deleted in T cells demonstrate enhanced responses to a tumor vaccine and subsequently reject tumors more robustly than Wt mice. These findings suggest that targeting Spry1 might prove to be a novel means of enhancing tumor immunotherapy.

SUBMITTER: Collins S

PROVIDER: S-EPMC3499516 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Regulation of CD4⁺ and CD8⁺ effector responses by Sprouty-1.

Collins Sam S Waickman Adam A Basson Albert A Kupfer Abraham A Licht Jonathan D JD Horton Maureen R MR Powell Jonathan D JD

PloS one 20121115 11

TCR-induced NF-AT activation leads to the expression of both activating and inhibitory proteins. Previously, we had identified Egr-2 and Egr-3 as NF-AT-induced transcription factors which promote the inhibition of T cell activation. In this report we identify Sprouty1 as a downstream target of Egr-3. CD4⁺ T cells lacking Spry1 demonstrate enhanced proliferation and cytokine production. Likewise, Spry1(Flox/Flox) Lck Cre CD8⁺ T cells display increased cytolytic activity. Mechanistically, Spry1 ac ...[more]

PMID: 23166773

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Project description:Purpose:Injection of an antigen into the anterior chamber of the eye induces a peripheral antigen-specific immune modulation mechanism, known as anterior chamber-associated immune deviation (ACAID). Delayed-type hypersensitivity experiments argue that the subretinal space (SR) of the eye displays properties similar to ACAID. However, no investigation was performed regarding the differential impact of a subretinal antigen injection on peripheral CD4+ versus CD8+ T cells, on the potential immune deviation regarding Th profiles, and on the antigen-specificity of the inhibition. A better understanding of these mechanisms is crucial to improve safety and immunomonitoring of ongoing therapeutic approaches targeting the SR. The aim of this study is to characterize the proliferative capacities and cytokine patterns of antigen-specific CD4+ and CD8+ T cells after a subretinal injection of antigen in mice. Methods:Ubiquitously Transcribed tetratricopeptide repeat gene Y-linked (UTY) and DEAD Box polypeptide 3 Y-linked (DBY) peptides which respectively include MHCI- and MHCII-restricted T-cell epitopes of the mouse HY male antigen, were injected into the subretinal space of C57BL/6 female mice. 2?weeks later, these mice were immunized subcutaneously with these peptides and compared to control mice. A week later, T-cell immune responses were analyzed by IFN? ELISpot assays and cytokine measurements (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17a, IFN?, TNF?, GM-CSF, and MCP-1) in the spleen and with proliferation assays in draining lymph nodes. Results:Immune cells from mice that received HY peptides in the SR before immunization, compared with those from control immunized mice, secreted significantly smaller quantities of Th1/Tc1, Th2/Tc2, and Th17/Tc17 cytokines, and HY-specific CD4+ T cells proliferated less in response to HY peptides. Conclusion:Taken together, our data clearly demonstrate that the subretinal injection of HY peptides induces a systemic HY-specific inhibition of conventional Th profiles and CD8+ T cells. We propose to call this phenomenon SRAII, for subretinal-associated immune inhibition.

Dataset Information

Regulation of CD4? and CD8? effector responses by Sprouty-1.

Publications

Regulation of CD4⁺ and CD8⁺ effector responses by Sprouty-1.

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