Vdovenko Daria, Stefańska Monika, Wijnen Winandus J, Zarak-Crnkovic Martina, Bachmann Marta, Kania Gabriela, Camici Giovanni G, Lüscher Thomas F, Eriksson Urs, Błyszczuk Przemysław
Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland.
J Immunol. 2025 Aug 1;214(8):1926-1936. doi: 10.1093/jimmun/vkaf150.
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.
Th1和Th17细胞介导的自身免疫对心肌炎的诱导至关重要。抗原呈递细胞（APC）释放的白细胞介素（IL）-12和IL-23与Th1和Th17谱系的分化有关。在本研究中，我们利用心脏自身抗原肌球蛋白重链α（α-MyHC）脉冲处理的骨髓来源树突状细胞（bmDC）以及野生型、IL-12p35-/-和IL-23p19-/-小鼠，来研究IL-12和IL-23对实验性自身免疫性心肌炎（EAM）中CD4+T细胞的影响。所有接受α-MyHC脉冲处理的bmDC的小鼠（小家鼠）均发生急性心肌炎，并且心脏组织中积累了干扰素（IFN）-γ阳性和IL-17A阳性的CD4+T细胞。与用野生型bmDC免疫相比，α-MyHC脉冲处理的IL-23p19-/-bmDC的过继转移导致受体小鼠心脏中IL-17A+CD4+T细胞数量减少，浸润的T淋巴细胞减少了两倍，尽管CD45+白细胞的浸润计数未受影响。相比之下，IL-12p35-/-bmDC诱导产生IFN-γ的CD④+T细胞较少，但不影响T淋巴细胞浸润。此外，与野生型小鼠相比，在过继转移α-MyHC脉冲处理的IL-23p19-/-bmDC后，IL-23p19-/-受体小鼠心脏中浸润的CD3+T细胞减少，但总CD45+细胞未减少。同样，在EAM的转基因TCRM模型中，TCRMxIL-23p19-/-小鼠的心肌炎严重程度降低，心脏中的T淋巴细胞减少，这表明在缺乏IL-23的情况下T细胞迁移受损。我们在体外验证了IL-23对活化的CD4+T细胞的促迁移作用，并证明了Rho GTP酶在这一过程中的重要作用。我们的研究结果为IL-23在自身免疫性心肌炎中的促炎活性提供了新的见解，突出了其在促进T细胞迁移中的独特作用。
