J Immunol. 2025 Jul 21:vkaf150. doi: 10.1093/jimmun/vkaf150. Online ahead of print.
ABSTRACT
Th1 and Th17 cell-mediated autoimmunity is critical for myocarditis induction. Antigen-presenting cell (APCs)-released interleukin (IL)-12 and IL-23 are implicated in the differentiation of Th1 and Th17 lineages. In this study, we utilized cardiac self-antigen myosin heavy chain alpha (α-MyHC)-pulsed bone marrow-derived dendritic cells (bmDCs) and wild-type, IL-12p35-/-, and IL-23p19-/- mice to investigate the influence of IL-12 and IL-23 on CD4+ T cells in experimental autoimmune myocarditis (EAM). All mice (Mus musculus) receiving α-MyHC-pulsed bmDCs developed acute myocarditis and accumulated interferon (IFN)-γ-positive and IL-17A-positive CD4+ T cells in cardiac tissue. Compared to immunization with wild-type bmDCs, adoptive transfer of α-MyHC-pulsed IL-23p19-/- bmDCs resulted in decreased numbers of IL-17A+CD4+ T cells and in a twofold reduction of infiltrating T lymphocytes in the hearts of recipient mice, despite unaffected infiltration count of CD45+ leukocytes. In contrast, IL-12p35-/- bmDCs induced fewer IFN-γ-producing CD4+ T cells but did not affect T lymphocyte infiltration. Furthermore, IL-23p19-/- recipient mice showed reduced heart-infiltrating CD3+ T cells, but not total CD45+, compared to wild-type mice after adoptive transfer of α-MyHC-pulsed IL-23p19-/- bmDCs. Likewise, in the transgenic TCRM model of EAM, TCRMxIL-23p19-/- mice showed reduced myocarditis severity and fewer T lymphocytes in their hearts pointing to impaired T cell trafficking in absence of IL-23. We validated the pro-migratory effect of IL-23 on activated CD4+ T cells in vitro and demonstrated an essential role of Rho GTPases in this process. Our findings provide new insights into the pro-inflammatory activity of IL-23 in autoimmune myocarditis, highlighting its unique role in promoting T cell migration.
PMID:40690778 | DOI:10.1093/jimmun/vkaf150