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

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 ICOS⁺CD45RA⁺CD31⁺ recent thymic emigrant (RTE) Tresps into CD45RA^-CD31^- memory Tresps affects the percentages of ICOS⁺ Tresps within total CD4⁺ T cells. Three different pathways (pathway 1 via CD45RA^-CD31⁺ memory Tresps, pathway 2 via direct proliferation and pathway 3 via resting mature naïve CD45RA⁺CD31^- (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 CD45RA^-CD31⁺ memory Tresps and direct proliferation, leaving an age-independently increased differentiation into CD45RA^-CD31^- 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 CD45RA^-CD31^- 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.