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
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.
|ISBN||1664-3224 (Electronic) 1664-3224 (Linking)|
|Authors||Masle-Farquhar, E.; Jeelall, Y.; White, J.; Bier, J.; Deenick, E. K.; Brink, R.; Horikawa, K.; Goodnow, C. C.|
|Publisher Name||Frontiers in Immunology|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/36960072|