Schematic representation of CD4⁺ T-cell involvement in cGVHD pathogenesis. Naive T cells traffic to local lymph nodes (A), where they recognize recipient minor antigen (mAg) presented by APCs (B). (C) Primed naive cells convert to mAg-specific effector cells and exit the lymph nodes. (D-E) In aGVHD, CD8⁺ effectors migrate along a CXCL10 chemokine gradient toward the skin (D) and in cGVHD, CD4⁺ effectors are preferentially recruited via CXCL9, CXCL10, and CXCL11 chemokine gradients (E). (F) On entrance into the skin, CD4/CD8⁺ T cells recognize recipient mAg expressed on MHC I and MHC II, respectively. (G) Effectors then direct tissue-specific killing, promoting local cytokine and chemokine production and setting up a cycle of tissue destruction and further effector recruitment.