Macrophage MHC and T-Cell Receptors Essential for Rejection of Allografted Skin and Lymphoma

Abstract

Skin or organ allograft rejection is dependent on noncytotoxic CD4(+) T cells, but the mechanisms of recognition and rejection remain elusive. Previously, we demonstrated C57BL/6 (H-2D(b)K(b)) macrophage-mediated, cell-to-cell contact-dependent, d haplotype-specific lysis of allografts (e.g., BALB/c skin and Meth A cells; H-2D(d)K(d)) in the rejection site and isolated two cDNA clones encoding receptors on macrophages for H-2D(d) and H-2K(d), macrophage major histocompatibility complex receptor (MMR) 1 and 2, respectively. To elucidate the role of MMR2 and T-cell receptors (TCRs) in graft rejection, we generated MMR2 knockout (KO) mice on a C57BL/6 background and transplanted D(d), K(d), or D(d)K(d) transgenic C57BL/6 skin or EL-4 lymphoma cells onto or into these KO mice. MMR2 KO mice lacking MMR2 mRNA or protein expression in their monocytes had no obvious abnormalities in terms of cell number in or composition of their lymphoid tissues or in T lymphocyte responses to alloantigen or nonalloantigen, whereas they failed to reject K(d) transgenic skin grafts. Surprisingly, they also lacked MMR1 mRNA and protein expression in their monocytes and failed to reject D(d) or D(d)K(d) transgenic skin grafts. However, they did reject skin grafts from mice expressing H-2I(d), minor H(d), or third-party major histocompatibility complex. On the contrary, D(d)-, K(d)-, or D(d)K(d)-EL-4 cells injected intradermally or intraperitoneally into MMR2 KO mice were rejected by TCR(αβ)(+)/CD8(+) T cells in a transgene number-dependent and MMR-independent manner. These results demonstrate that MMRs on monocytes/macrophages and TCRs on cytotoxic T lymphocytes in mice were essential for recognition and rejection of allografted skin and lymphoma, respectively.