Cytokine secretion

FIGURE 16-7 The mixed lymphocyte reaction (MLR). In a one-way primary MLR, stimulator cells (from donor Y) activate and cause the expansion of two types of responder T cells (from donor X). CD4+ T cells from donor X react to donor Y class II molecules, and CD8+ T lymphocytes from donor X react to donor Y class I MHC molecules. The CD4+ T cells differentiate into cytokine-secreting helper T cells, and the CD8+ T cells differentiate into CTLs. APC, antigen-presenting cell.

hypersensitivity (DTH) reaction (see Chapters 10 and 18). Alloreactive CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), which kill nucleated cells in the graft that express the allogeneic class I MHC molecules. CTLs also secrete inflammatory cytokines, which can contribute to graft damage.

Only CTLs that are generated by direct allogeneic MHC recognition can kill graft cells, whereas CTLs or helper T cells generated by either direct or indirect alloantigen recognition can cause cytokine-mediated damage to grafts. CD8+ CTLs that are generated by direct allorecognition recognize graft alloantigens and can, therefore, kill graft cells that express these same alloantigens. In contrast, any CD8+ CTLs that are generated by the indirect pathway are self MHC restricted, and they will not be able to kill the foreign graft cells because these cells do not express self MHC alleles displaying allogeneic peptides. Therefore, when alloreactive T cells are stimulated by the indirect pathway, the principal mechanism of rejection is not CTL-mediated killing of graft cells but inflammation caused by the cytokines produced by either CD8+ or CD4+ effector T cells. Presumably, these effector cells infiltrate the graft and recognize graft alloantigens being displayed by host APCs that have also entered the graft. The relative importance of the direct and indirect pathways in graft rejection is not definitively established. It may be that CD8+ CTLs induced by direct recognition of alloantigens are most important for acute cellular rejection of allografts, in which killing of graft cells is a prominent component, whereas CD4+ effector T cells stimulated by the indirect pathway play a greater role in chronic rejection. These differences may be of clinical significance because conventional immunosuppressive therapy for graft rejection seems to preferentially suppress CD8+ CTL responses induced by direct allorecognition and is less effective against CD4+ T cells activated by the indirect pathway.

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