CARD11 gain-of-function mutation drives cell-autonomous accumulation of PD-1+ ICOShigh activated T cells, T-follicular, T-regulatory and T-follicular regulatory cells

Frontiers in Immunology

Immunology

Christopher Carl Goodnow¹  Jacqueline White²  Elissa K. Deenick²  Robert Brink²  Julia Bier²  Etienne Masle-Farquhar²  Yogesh Jeelall³  Keisuke Horikawa³ 

[1] Garvan Institute of Medical Research, Sydney, NSW, Australia;Cellular Genomics Futures Institute, University of New South Wales, Sydney, Australia;Garvan Institute of Medical Research, Sydney, NSW, Australia;School of Clinical Medicine, St Vincent’s Healthcare Clinical, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia;John Curtin School of Medical Research, Immunology Department, The Australian National University, Canberra, ACT, Australia;

关键词: CARD11;    mutation;    gain-of-function;    regulatory T cell;    follicular T cell;    germinal center;    lymphoproliferation;    lymphoma;   

DOI  :  10.3389/fimmu.2023.1095257

 received in 2022-11-11, accepted in 2023-02-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionGermline CARD11 gain-of-function (GOF) mutations cause B cell Expansion with NF-κB 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.MethodsHere, we studied B and T lymphocytes in mice with a germline Nethyl-N-nitrosourea (ENU)-induced Card11M365K 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 discussionOur results demonstrate that CARD11.M365K is a GOF protein that increases B and T lymphocyte activation and proliferation following antigen receptor stimulation. Germline Card11M365K mutation was insufficient alone to cause B or T-lymphoma, but increased accumulation of germinal center (GC) B cells in unimmunized and immunized mice. Card11M365K mutation caused cell-intrinsic over-accumulation of activated T cells, T regulatory (TREG), T follicular (TFH) and T follicular regulatory (TFR) 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 TFH, TREG and TFR 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.

【 授权许可】

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Copyright © 2023 Masle-Farquhar, Jeelall, White, Bier, Deenick, Brink, Horikawa and Goodnow