In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4+ TH1 cell response.
Sci Immunol
; 6(66): eabe8219, 2021 Dec 03.
Article
en En
| MEDLINE
| ID: mdl-34860579
ABSTRACT
Although CD8+ T cells undergo autonomous clonal proliferation after antigen stimulation in vivo, the expansion of activated CD4+ T cells is limited by intrinsic factors that are poorly characterized. Using genome-wide CRISPR-Cas9 screens and an in vivo system modeling of antigen-experienced CD4+ T cell recruitment and proliferation during a localized immune response, we identified suppressor of cytokine signaling 1 (SOCS1) as a major nonredundant checkpoint imposing a brake on CD4+ T cell proliferation. Using antiinterleukin-2 receptor (IL-2R) blocking antibodies, interferon-γ receptor (IFN-γR) knockout mice, and transcriptomic analysis, we show that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals to block multiple downstream signaling pathways abrogating CD4+ T helper 1 (TH1) cell response. Inactivation of SOCS1 in both murine and human CD4+ T cell antitumor adoptive therapies restored intratumor accumulation, proliferation/survival, persistence, and polyfunctionality and promoted rejection of established tumors. However, in CD8+ T cells, SOCS1 deletion did not affect the proliferation but rather improved survival and effector functions, which allowed for optimal therapeutic outcome when associated with SOCS1 inactivation in CD4+ T cells. Together, these findings identify SOCS1 as a major intracellular negative checkpoint of adoptive T cell response, opening new possibilities to optimize CAR-T cell therapy composition and efficacy.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos T CD4-Positivos
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Células TH1
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas
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Proteína 1 Supresora de la Señalización de Citocinas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Sci Immunol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia