Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate.
T-cell interactions with antigen-presenting cells are important for CD8 T-cell effector or memory fate determination. The integrin leukocyte function-associated antigen-1 (LFA-1) mediates T-cell adhesion but the contribution of LFA-1-induced signaling pathways to T-cell responses is poorly understood. Here we demonstrate that proline-rich tyrosine kinase-2 (PYK2) deficiency impairs CD8 T-cell activation by synergistic LFA-1 and T-cell receptor stimulation. Furthermore, PYK2 is essential for LFA-1-mediated CD8 T-cell adhesion and LFA-1 costimulation of CD8 T-cell migration. During lymphocytic choriomeningitis virus infection in vivo, PYK2 deficiency results in a specific loss of short-lived effector CD8 T cells but does not affect memory-precursor CD8 T-cell development. Similarly, lack of LFA-1 primarily impairs the generation of short-lived effector cells. Thus, PYK2 facilitates LFA-1-dependent CD8 T-cell responses and promotes CD8 T-cell short-lived effector fate, suggesting that PYK2 may be an interesting therapeutic target to suppress exacerbated CD8 T-cell responses.
Beinke
Sören
S
Department of Medicine, Division of Rheumatology, The Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, and Graduate Program in Biomedical Sciences, University of California, San Francisco, CA 94143-0795, USA.
Phee
Hyewon
H
Clingan
Jonathan M
JM
Schlessinger
Joseph
J
Matloubian
Mehrdad
M
Weiss
Arthur
A
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D007156:Immunologic Memory; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse
Mol Cell Biol. 2009 Oct;29(20):5578-89
19667077
Immunol Rev. 2010 May;235(1):190-205
20536564
J Biol Chem. 1998 Jun 5;273(23):14301-8
9603937
J Cell Biol. 1996 May;133(4):895-910
8666673
J Exp Med. 1996 Apr 1;183(4):1415-26
8666900
J Immunol. 2002 Jul 1;169(1):292-300
12077257
Science. 2000 Oct 6;290(5489):92-7
11021806
Immunity. 1998 Jan;8(1):89-95
9462514
Eur J Immunol. 1999 Mar;29(3):809-14
10092083
J Immunol. 1998 Oct 1;161(7):3652-8
9759889
J Exp Med. 2008 Mar 17;205(3):625-40
18316415
J Immunol. 1999 Nov 1;163(9):5029-38
10528208
Nat Immunol. 2010 Jun;11(6):503-11
20431621
J Immunol. 2007 Jan 15;178(2):778-87
17202339
Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68
15688067
Science. 2007 Mar 23;315(5819):1687-91
17332376
J Immunol. 1996 Dec 15;157(12):5375-86
8955185
Nature. 1996 Oct 10;383(6600):547-50
8849729
Nat Immunol. 2003 Apr;4(4):355-60
12640450
J Cell Sci. 2009 Jan 15;122(Pt 2):215-25
19118214
J Cell Biol. 2002 Apr 15;157(2):265-75
11940607
Immunity. 2008 Jun;28(6):810-21
18549800
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10740-5
12960403
Nature. 2009 Mar 12;458(7235):211-4
19182777
Eur J Immunol. 1998 Nov;28(11):3867-77
9842930
J Immunol. 2008 Apr 1;180(7):4507-13
18354172
Immunity. 2003 Nov;19(5):761-9
14614862
J Exp Med. 1997 Mar 17;185(6):1055-63
9091579
Blood. 1998 Feb 1;91(3):791-7
9446638
Nature. 2006 Apr 13;440(7086):890-5
16612374
Eur J Immunol. 1999 Jan;29(1):45-53
9933085
J Immunol. 1997 Aug 15;159(4):1753-7
9257837
J Exp Med. 1997 Apr 7;185(7):1253-9
9104812
J Exp Med. 2006 Sep 4;203(9):2135-43
16908626
Immunity. 1997 Oct;7(4):549-57
9354475
J Immunol. 1999 Jan 15;162(2):1120-6
9916742
J Cell Biol. 2004 Jul 19;166(2):273-82
15249579
Immunity. 2008 Feb;28(2):258-70
18275834
Annu Rev Immunol. 2007;25:171-92
17129182
J Immunol. 2000 Dec 15;165(12):6833-9
11120806
Nat Immunol. 2005 May;6(5):465-71
15821738
Nat Immunol. 2000 Jul;1(1):31-6
10881171
Immunol Rev. 2010 May;235(1):219-33
20536566
Nat Immunol. 2001 May;2(5):423-9
11323696
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12436-41
19617540
J Biol Chem. 1997 Jan 3;272(1):228-32
8995252
J Immunol. 1999 Nov 1;163(9):4826-32
10528183
Mol Biol Cell. 1999 Jun;10(6):1891-907
10359604
Nat Immunol. 2001 May;2(5):415-22
11323695