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

Yang Wang, Dan Li, Roza Nurieva, Justin Yang, Mehmet Sen, Roberto Carreño, Sijie Lu, Bradley W. McIntyre, Jeffrey J. Molldrem, Glen B. Legge, Qing Ma

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12645-12653
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number19
DOIs
StatePublished - May 8 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility

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