Journal
SCIENCE SIGNALING
Volume 15, Issue 742, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abl5343
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Funding
- INSERM
- Foundation ARSEP
- Association pour la Recherche sur le Cancer (ARC)
- Agence Nationale de la Recherche [ANR-20-CE15-0002, ANR-20-CE15-0005]
- Intramural Research Program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development
- Marie Curie International Reintegration Grant
- China Scholarship Council
- French Ministry of Higher Education and Research
- Agence Nationale de la Recherche (ANR) [ANR-20-CE15-0005] Funding Source: Agence Nationale de la Recherche (ANR)
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This study reveals the role of the protein THEMIS in regulating different subsets of CD4(+) T cells. THEMIS promotes T(H)1 cell responses and contributes to the development of autoimmune responses.
Signals that determine the differentiation of naive CD4(+) T helper (T-H) cells into specific effector cell subsets are primarily stimulated by cytokines, but additional signals are required to adjust the magnitude of T-H cell responses and set the balance between effective immunity and immunological tolerance. By inducing the post-thymic deletion of the T cell lineage signaling protein THEMIS, we showed that THEMIS promoted the development of optimal type 1 immune responses to foreign antigens but stimulated signals that favored encephalitogenic responses to self-neuroantigens. THEMIS was required to stimulate the expression of the gene encoding the transcriptional regulator T-BET and the production of the cytokine interferon-gamma (IFN-gamma), and it enhanced the ability of encephalitogenic CD4(+) T cells to migrate into the central nervous system. Consistently, analysis of THEMIS expression in polarized CD4(+) T cells showed that THEMIS was selectively increased in abundance in T(H)1 cells. The stimulation of predifferentiated effector CD4(+) T cells with antigen-presenting cells revealed a stimulatory function for THEMIS on type 1 cytokine responses, similar to those observed ex vivo after immunization. In contrast, THEMIS exerted opposing effects on naive CD4(+) T cells in vitro by inhibiting the T cell receptor (TCR)-mediated signals that lead to T(H)1 cell responses. These data suggest that THEMIS exerts TCR-independent functions in effector T cells, which increase the magnitude of normal and pathogenic T(H)1 cell-mediated responses.
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