TGF-ß-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.
Immunity
; 55(1): 115-128.e9, 2022 01 11.
Article
em En
| MEDLINE
| ID: mdl-35021053
ABSTRACT
The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes TfhB cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos do Interstício Tumoral
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Fator de Crescimento Transformador beta
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Linfócitos T Auxiliares-Indutores
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Centro Germinativo
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Proteínas de Ligação à Região de Interação com a Matriz
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Estruturas Linfoides Terciárias
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article