Impaired immune responses toward alloantigens and tumor cells but normal thymic selection in mice deficient in the beta2 integrin leukocyte function-associated antigen-1.
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.
Shier
P
P
The R.W. Johnson Pharmaceutical Research Institute, San Diego, CA 92121, USA.
Otulakowski
G
G
Ngo
K
K
Panakos
J
J
Chourmouzis
E
E
Christjansen
L
L
Lau
C Y
CY
Fung-Leung
W P
WP
D000818:Animals; D002449:Cell Aggregation; D002634:Chemotaxis, Leukocyte; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
D016169:Lymphocyte Function-Associated Antigen-1