T cell exhaustion dynamics in systemic autoimmune disease

Unlike in infection and cancer, T cell exhaustion in autoimmune disease has not been clearly defined. Here we set out to understand inhibitory protein (PD-1, Tim3, CTLA4, Lag3) expression in CXCR5- and CXCR5+ CD8 and CD4 T cells in systemic lupus erythematosus. CXCR5+ CD8 and CD4 T cells express PD-1 and engage B cells in germinal center reactions, leading to autoantibody formation in autoimmunity. We hypothesized that CXCR5+ CD8 T cells develop an exhausted phenotype as SLE autoimmunity expands from initial to chronic, self-perpetuating disease due to chronic self-antigen exposure. Our results indicate that there is no exhaustion frequency differences between sexes, although disease kinetics vary by sex. CXCR5+ CD8 T cells express primarily IFNγ, known to promote autoimmune disease development, whereas CXCR5-CD8 T cells express TNFα and IFNγ as disease progresses from 2-6 months. Tim3 is the highest expressed inhibitory marker for all CD4 and CD8 T cell populations demonstrating potential for terminally exhausted populations. CTLA4 expression on CD4 T cells suggests potential tolerance induction in these cells. We identified exhaustion phenotypes within autoimmune disease that progress with increasing lupus erythematosus severity and possibly provide a feedback mechanism for immunological tolerance. Highlights 1. CXCR5- and CXCR5+ CD8 T cells expand with rate of disease in SLE mouse model. 2. CXCR5+ CD8 T cells are low contributors to TNFα disease progression unlike CXCR5-CD8 T cells but may increase disease mechanisms through high IFNγ production. 3. Inhibitory markers upregulate in frequency with the highest amounts seen in Tim3+ populations. Tim3+Lag3+ expression may be an indicator of terminal differentiation for all populations. 4. Inhibitory marker expression frequency was unrelated to sex. ### Competing Interest Statement The authors have declared no competing interest. * CTLA4 : cytotoxic T-lymphocyte-associated protein 4, CD152 HBV : hepatitis B virus IFNγ : interferon gamma IL-1β : interleukin-1 beta Lag3 : lymphocyte activation protein 3, CD223 LCMV : lymphocytic choriomeningitis virus MRL/MpJ : MRL/MpJ- Faslpr, MRL, Murphy Roths Large MRL/lpr : MRL/MpJ-Faslpr/J, lymphoproliferation PD-1 : programmed cell death protein 1, CD279 SIV : simian immunodeficiency virus SLE : systemic lupus erythematosus Tex : terminal exhaustion Tfh : T follicular helper Tim3 : T-cell immunoglobulin and mucin domain 3, CD366 TNFα : tumor necrosis factor alpha Tpex : pre-exhausted