| First Author | Masle-Farquhar E | Year | 2023 |
| Journal | Front Immunol | Volume | 14 |
| Pages | 1095257 | PubMed ID | 36960072 |
| Mgi Jnum | J:342748 | Mgi Id | MGI:7447661 |
| Doi | 10.3389/fimmu.2023.1095257 | Citation | Masle-Farquhar E, et al. (2023) CARD11 gain-of-function mutation drives cell-autonomous accumulation of PD-1(+) ICOS(high) activated T cells, T-follicular, T-regulatory and T-follicular regulatory cells. Front Immunol 14:1095257 |
| abstractText | INTRODUCTION: Germline CARD11 gain-of-function (GOF) mutations cause B cell Expansion with NF-kappaB and T cell Anergy (BENTA) disease, whilst somatic GOF CARD11 mutations recur in diffuse large B cell lymphoma (DLBCL) and in up to 30% of the peripheral T cell lymphomas (PTCL) adult T cell leukemia/lymphoma (ATL), cutaneous T cell lymphoma (CTCL) and Sezary Syndrome. Despite their frequent acquisition by PTCL, the T cell-intrinsic effects of CARD11 GOF mutations are poorly understood. METHODS: Here, we studied B and T lymphocytes in mice with a germline Nethyl-N-nitrosourea (ENU)-induced Card11(M365K) mutation identical to a mutation identified in DLBCL and modifying a conserved region of the CARD11 coiled-coil domain recurrently mutated in DLBCL and PTCL. RESULTS AND DISCUSSION: Our results demonstrate that CARD11.M365K is a GOF protein that increases B and T lymphocyte activation and proliferation following antigen receptor stimulation. Germline Card11(M365K) mutation was insufficient alone to cause B or T-lymphoma, but increased accumulation of germinal center (GC) B cells in unimmunized and immunized mice. Card11(M365K) mutation caused cell-intrinsic over-accumulation of activated T cells, T regulatory (T(REG)), T follicular (T(FH)) and T follicular regulatory (T(FR)) cells expressing increased levels of ICOS, CTLA-4 and PD-1 checkpoint molecules. Our results reveal CARD11 as an important, cell-autonomous positive regulator of T(FH), T(REG) and T(FR) cells. They highlight T cell-intrinsic effects of a GOF mutation in the CARD11 gene, which is recurrently mutated in T cell malignancies that are often aggressive and associated with variable clinical outcomes. |
