Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling.
CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25(+)Foxp3(+)) from naive CD4 T cells (CD25(-)Foxp3(-)) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2-inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.
Department of Pathology and Cell Biology, University of South Florida, Tampa, FL, USA.
Kenrick
K
Semple
Antony
A
Nguyen
Yu
Y
Yu
Honglin
H
Wang
Claudio
C
Anasetti
Xue-Zhong
XZ
Yu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019869:Phosphatidylinositol 3-Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
J Immunol. 2001 May 1;166(9):5331-5
11313368
Am J Transplant. 2009 Dec;9(12):2837-44
19845593
J Immunol. 2007 Feb 15;178(4):2018-27
17277105
Science. 1999 Jan 29;283(5402):680-2
9924026
J Exp Med. 2006 Sep 4;203(9):2121-33
16908623
J Immunol. 2003 Mar 15;170(6):3002-6
12626553
Nat Rev Immunol. 2001 Dec;1(3):220-8
11905831
Immunol Rev. 2006 Aug;212:86-98
16903908
Blood. 2005 Jan 1;105(1):13-21
15353480
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
J Clin Invest. 2004 Jun;113(11):1624-30
15173889
Biol Blood Marrow Transplant. 2010 Feb;16(2):170-8
19804837
J Immunol. 2003 Oct 1;171(7):3348-52
14500627
Nat Immunol. 2005 Apr;6(4):331-7
15785758
J Immunol. 2004 May 1;172(9):5149-53
15100250
Nat Immunol. 2005 Dec;6(12):1219-27
16244650
J Exp Med. 2009 Dec 21;206(13):3001-14
19995950
J Exp Med. 2004 May 17;199(10):1401-8
15148338
J Immunol. 2008 Aug 15;181(4):2285-91
18684917
Nat Immunol. 2001 Apr;2(4):325-32
11276203
Nat Rev Immunol. 2003 Jul;3(7):544-56
12876557
Nat Immunol. 2002 Mar;3(3):259-64
11828322
Nat Immunol. 2005 Feb;6(2):152-62
15640801
J Exp Med. 2010 Aug 2;207(8):1701-11
20660617
Immunol Rev. 2009 May;229(1):41-66
19426214
Immunity. 2000 Apr;12(4):431-40
10795741
J Exp Med. 2007 Aug 6;204(8):1765-74
17620363
J Immunol. 2001 Mar 15;166(6):3797-803
11238622
J Immunol. 2007 Apr 1;178(7):4022-6
17371955
Mol Cell Biol. 2009 Jul;29(13):3710-21
19398586
Nat Immunol. 2005 Nov;6(11):1142-51
16227984
Immunity. 2009 Dec 18;31(6):932-40
20064450
Blood. 2008 Jan 15;111(2):954-62
17928532
Immunity. 2005 Mar;22(3):329-41
15780990
J Immunol. 2010 Apr 15;184(8):4074-7
20228198
J Exp Med. 2005 Jan 3;201(1):127-37
15630140
Immunity. 2009 Dec 18;31(6):921-31
20064449