title: LFA-1 affinity regulation is necessary for the activation and proliferation of naive T cells.
abstract: The activation of LFA-1 (lymphocyte function-associated antigen) is a critical event for T cell co-stimulation. The mechanism of LFA-1 activation involves both affinity and avidity regulation, but the role of each in T cell activation remains unclear. We have identified antibodies that recognize and block different affinity states of the mouse LFA-1 I-domain. Monoclonal antibody 2D7 preferentially binds to the low affinity conformation, and this specific binding is abolished when LFA-1 is locked in the high affinity conformation. In contrast, M17/4 can bind both the locked high and low affinity forms of LFA-1. Although both 2D7 and M17/4 are blocking antibodies, 2D7 is significantly less potent than M17/4 in blocking LFA-1-mediated adhesion; thus, blocking high affinity LFA-1 is critical for preventing LFA-1-mediated adhesion. Using these reagents, we investigated whether LFA-1 affinity regulation affects T cell activation. We found that blocking high affinity LFA-1 prevents interleukin-2 production and T cell proliferation, demonstrated by TCR cross-linking and antigen-specific stimulation. Furthermore, there is a differential requirement of high affinity LFA-1 in the activation of CD4(+) and CD8(+) T cells. Although CD4(+) T cell activation depends on both high and low affinity LFA-1, only high affinity LFA-1 provides co-stimulation for CD8(+) T cell activation. Together, our data demonstrated that the I-domain of LFA-1 changes to the high affinity state in primary T cells, and high affinity LFA-1 is critical for facilitating T cell activation. This implicates LFA-1 activation as a novel regulatory mechanism for the modulation of T cell activation and proliferation.
authors.affiliation: Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Justin
authors.initials: J
authors.lastname: Yang
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sen
authors.forename: Roberto
authors.initials: R
authors.lastname: Carreño
authors.forename: Sijie
authors.initials: S
authors.lastname: Lu
authors.forename: Bradley W
authors.initials: BW
authors.lastname: McIntyre
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.forename: Glen B
authors.initials: GB
authors.lastname: Legge
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002448:Cell Adhesion; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell