Sex-specific differences in ICOS T helper cell differentiation in systemic lupus erythematosus patients with low disease activity.

Systemic lupus erythematosus (SLE) is a sex biased chronic autoimmune disease affecting predominantly females during reproductive ages. Changes in the ratio of inducible costimulatory molecule (ICOS) regulatory (Treg) and non-regulatory responder (Tresp) CD4 T cells proved to be crucial for the occurrence of high disease activity. Here, we investigated how the differentiation of ICOSCD45RACD31 recent thymic emigrant (RTE) Tresps into CD45RACD31 memory Tresps affects the percentages of ICOS Tresps within total CD4 T cells. Three different pathways (pathway 1 via CD45RACD31 memory Tresps, pathway 2 via direct proliferation and pathway 3 via resting mature naïve CD45RACD31 (MN) cells) were examined in healthy controls and SLE remission patients separated by sex. In female SLE remission patients, immunosuppressive therapy inhibited the ICOS RTE differentiation via CD45RACD31 memory Tresps and direct proliferation, leaving an age-independently increased differentiation into CD45RACD31 memory Tresps by conversion of resting MN Tresps compared with healthy controls. Due to exhaustion of this pathway with age, no age-dependent change in the percentages of ICOS Tresps within total CD4 T cells could be found. In contrast, no age-independently increased differentiation could be detected in men due to sufficient immunosuppression of all three pathways. This allowed an age-dependent differentiation of ICOS RTE Tresps into CD45RACD31 memory Tresps by conversion of resting MN Tresps, resulting in age-dependently increasing percentages of ICOS Tresps within total CD4 T cells. We hypothesize that the sex-specific differential effect of immunosuppression on the differentiation of ICOS Tresps may explain the sex- and age-dependent occurrence of high disease activity.