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Use of a 1 Integrin-deficient Human T Cell to Identify 1 Integrin Cytoplasmic Domain Sequences Critical for Integrin Function

Nadine C. Romzek,^* Estelle S. Harris, Cheryl L. Dell, Jeffrey Skronek, Elizabeth Hasse,^§ Pamela J. Reynolds,^§ Stephen W. Hunt III, and Yoji Shimizu^*

 ^*Department of Laboratory Medicine and Pathology, Center for Immunology and Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455;  Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105;  Department of Medicine, Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84132; and  ^§Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109

T cell activation rapidly and transiently regulates the functional activity of integrin receptors. Stimulation of CD3/T cell receptor, CD2 or CD28, as well as activation with phorbol esters, can induce within minutes an increase in 1 integrin-mediated adhesion of T cells to fibronectin. In this study, we have produced and utilized a mutant of the Jurkat T cell line, designated A1, that lacks protein and mRNA expression of the 1 integrin subunit but retains normal levels of CD2, CD3, and CD28 on the cell surface. Activation-dependent adhesion of A1 cells to fibronectin could be restored upon transfection of a wild-type human 1 integrin cDNA. Adhesion induced by phorbol 12-myristate 13-acetate-, CD3-, CD2-, and CD28 stimulation did not occur if the carboxy-terminal five amino acids of the 1 tail were truncated or if either of two well-conserved NPXY motifs were deleted. Scanning alanine substitutions of the carboxy-terminal five amino acids demonstrated a critical role for the tyrosine residue at position 795. The carboxy-terminal truncation and the NPXY deletions also reduced adhesion induced by direct stimulation of the 1 integrin with the activating 1 integrin-specific mAb TS2/16, although the effects were not as dramatic as observed with the other integrin-activating signals. These results demonstrate a vital role for the amino-terminal NPXY motif and the carboxy-terminal end of the 1 integrin cytoplasmic domain in activation-dependent regulation of integrin-mediated adhesion in T cells. Furthermore, the A1 cell line represents a valuable new cellular reagent for the analysis of 1 integrin structure and function in human T cells.

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