IMPAIRED IMMUNE-RESPONSES TOWARD ALLOANTIGENS AND TUMOR-CELLS BUT NORMAL THYMIC SELECTION IN MICE DEFICIENT IN THE BETA(2) INTEGRIN LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1

We have generated mice deficient in the beta(2) integrin LFA-1 by targ eted disruption of the CD11a gene in embryonic stem cells, In vitro LF A-1 -/- cells exhibit a delayed proliferative response toward alloanti gens in the MLR. In vivo the host-vs-graft reaction toward injected al logeneic cells is also reduced, Alloantigen-specific CTLs generated fr om LFA-1 -/- mice are impaired in their cytotoxic activity toward allo geneic spleen cells as well as cell line targets, The proliferative re sponse of LFA-1 -/- splenocytes following stimulation by LPS, PMA plus ionomycin, or immobilized anti-CD3 epsilon mAb is normal, but Con A-s timulated proliferation is greatly diminished, We observe typical edem a formation in a delayed type hypersensitivity reaction to SRBC with n ormal extravasation of leukocytes and demonstrate recruitment of neutr ophils to an LPS-induced inflammatory site in these mice, suggesting t hat LFA-1 does not play an essential role in lymphocyte homing and leu kocyte extravasation. We further show that LFA-1 -/- mice are suscepti ble to metastasis of B16 melanoma tumors, although their in vitro NK c ell activity appears normal, A study of LFA-1 -/- mice expressing tran sgenic TCRs indicates that thymic maturation and selection of T cells are unaffected by the loss of LFA-1. Our results indicate that LFA-1 i s important for alloantigen-triggered T cell proliferation and cytotox icity, for Con A stimulation of T cells, and in tumor rejection, It do es not appear to play an essential role in lymphocyte homing and leuko cyte extravasation or in T cell maturation and selection in the thymus .