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Changes in the ratio of inducible costimulatory molecule (ICOS)<jats:sup>+<\/jats:sup> regulatory (Treg) and non-regulatory responder (Tresp) CD4<jats:sup>+<\/jats:sup> T cells proved to be crucial for the occurrence of high disease activity. Here, we investigated how the differentiation of ICOS<jats:sup>+<\/jats:sup>CD45RA<jats:sup>+<\/jats:sup>CD31<jats:sup>+<\/jats:sup> recent thymic emigrant (RTE) Tresps into CD45RA<jats:sup>\u2212<\/jats:sup>CD31<jats:sup>\u2212<\/jats:sup> memory Tresps affects the percentages of ICOS<jats:sup>+<\/jats:sup> Tresps within total CD4<jats:sup>+<\/jats:sup> T cells. Three different pathways (pathway 1 via CD45RA<jats:sup>\u2212<\/jats:sup>CD31<jats:sup>+<\/jats:sup> memory Tresps, pathway 2 via direct proliferation and pathway 3 via resting mature na\u00efve CD45RA<jats:sup>+<\/jats:sup>CD31<jats:sup>\u2212<\/jats:sup> (MN) cells) were examined in healthy controls and SLE remission patients separated by sex. In female SLE remission patients, immunosuppressive therapy inhibited the ICOS<jats:sup>+<\/jats:sup> RTE differentiation via CD45RA<jats:sup>\u2212<\/jats:sup>CD31<jats:sup>+<\/jats:sup> memory Tresps and direct proliferation, leaving an age-independently increased differentiation into CD45RA<jats:sup>\u2212<\/jats:sup>CD31<jats:sup>\u2212<\/jats:sup> 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<jats:sup>+<\/jats:sup> Tresps within total CD4<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> RTE Tresps into CD45RA<jats:sup>\u2212<\/jats:sup>CD31<jats:sup>\u2212<\/jats:sup> memory Tresps by conversion of resting MN Tresps, resulting in age-dependently increasing percentages of ICOS<jats:sup>+<\/jats:sup> Tresps within total CD4<jats:sup>+<\/jats:sup> T cells. We hypothesize that the sex-specific differential effect of immunosuppression on the differentiation of ICOS<jats:sup>+<\/jats:sup> Tresps may explain the sex- and age-dependent occurrence of high disease activity.<\/jats:p>","DOI":"10.1007\/s10238-024-01307-1","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T12:02:01Z","timestamp":1709294521000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-specific differences in ICOS+ T helper cell differentiation in systemic lupus erythematosus patients with low disease activity"],"prefix":"10.1007","volume":"24","author":[{"given":"Lisa","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"K\u00e4lble","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanns-Martin","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Zeier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Schaier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Steinborn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"issue":"9","key":"1307_CR1","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/ni0901-777","volume":"2","author":"CC Whitacre","year":"2001","unstructured":"Whitacre CC. 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