Impaired immune responses toward alloantigens and tumor cells but normal thymic selection in mice deficient in the beta2 integrin leukocyte function-associated …

P Shier, G Otulakowski, K Ngo, J Panakos… - … (Baltimore, Md.: 1950 …, 1996 - journals.aai.org
P Shier, G Otulakowski, K Ngo, J Panakos, E Chourmouzis, L Christjansen, CY Lau…
Journal of immunology (Baltimore, Md.: 1950), 1996journals.aai.org
We have generated mice deficient in the beta2 integrin LFA-1 by targeted disruption of the
CD11a gene in embryonic stem cells. In vitro LFA-1-/-cells exhibit a delayed proliferative
response toward alloantigens in the MLR. In vivo the host-vs-graft reaction toward injected
allogeneic cells is also reduced. Alloantigen-specific CTLs generated from LFA-1-/-mice are
impaired in their cytotoxic activity toward allogeneic spleen cells as well as cell line targets.
The proliferative response of LFA-1-/-splenocytes following stimulation by LPS, PMA plus …
Abstract
We have generated mice deficient in the beta2 integrin LFA-1 by targeted disruption of the CD11a gene in embryonic stem cells. In vitro LFA-1 -/- cells exhibit a delayed proliferative response toward alloantigens in the MLR. In vivo the host-vs-graft reaction toward injected allogeneic cells is also reduced. Alloantigen-specific CTLs generated from LFA-1 -/- mice are impaired in their cytotoxic activity toward allogeneic spleen cells as well as cell line targets. The proliferative response of LFA-1 -/- splenocytes following stimulation by LPS, PMA plus ionomycin, or immobilized anti-CD3epsilon mAb is normal, but Con A-stimulated proliferation is greatly diminished. We observe typical edema formation in a delayed type hypersensitivity reaction to SRBC with normal extravasation of leukocytes and demonstrate recruitment of neutrophils to an LPS-induced inflammatory site in these mice, suggesting that LFA-1 does not play an essential role in lymphocyte homing and leukocyte extravasation. We further show that LFA-1 -/- mice are susceptible to metastasis of B16 melanoma tumors, although their in vitro NK cell activity appears normal. A study of LFA-1 -/- mice expressing transgenic TCRs indicates that thymic maturation and selection of T cells are unaffected by the loss of LFA-1. Our results indicate that LFA-1 is important for alloantigen-triggered T cell proliferation and cytotoxicity, for Con A stimulation of T cells, and in tumor rejection. It does not appear to play an essential role in lymphocyte homing and leukocyte extravasation or in T cell maturation and selection in the thymus.
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