LFA-1 affinity regulation is necessary for the activation and proliferation of naive T cells

J Biol Chem. 2009 May 8;284(19):12645-53. doi: 10.1074/jbc.M807207200. Epub 2009 Mar 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology
  • Antibodies, Monoclonal / immunology
  • Antibody Affinity / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Adhesion
  • Flow Cytometry
  • Interleukin-2 / metabolism
  • Lymphocyte Activation / physiology*
  • Lymphocyte Function-Associated Antigen-1 / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / physiology

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Interleukin-2
  • Lymphocyte Function-Associated Antigen-1
  • Receptors, Antigen, T-Cell