title: High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.
abstract: The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept–resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies.
authors.forename: S M
authors.initials: SM
authors.lastname: Krummey
authors.forename: J A
authors.initials: JA
authors.lastname: Cheeseman
authors.forename: J A
authors.initials: JA
authors.lastname: Conger
authors.forename: P S
authors.initials: PS
authors.lastname: Jang
authors.forename: A K
authors.initials: AK
authors.lastname: Mehta
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: M L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D004351:Drug Resistance / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007156:Immunologic Memory / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000276:immunology / Q000628:therapy; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept
references.citation: Immunity. 2012 Feb 24;36(2):201-14
references.pmid: 22326581
references.citation: J Immunol. 2010 Aug 1;185(3):1375-8
references.pmid: 20601598
references.citation: Eur J Immunol. 2009 Aug;39(8):2076-82
references.pmid: 19672903
references.citation: Nat Immunol. 2007 Jun;8(6):639-46
references.pmid: 17486092
references.citation: Nat Immunol. 2007 Apr;8(4):388-97
references.pmid: 17322886
references.citation: Curr Opin Immunol. 2011 Dec;23(6):702-6
references.pmid: 21899997
references.citation: Nature. 2012 Apr 26;484(7395):514-8
references.pmid: 22466287
references.citation: Blood. 2012 Nov 29;120(23):4560-70
references.pmid: 23047820
references.citation: Transpl Int. 2012 Apr;25(4):455-63
references.pmid: 22348376
references.citation: J Immunol. 2006 Dec 1;177(11):7698-706
references.pmid: 17114440
references.citation: Immunol Rev. 2009 May;229(1):307-21
references.pmid: 19426230
references.citation: N Engl J Med. 2009 Aug 27;361(9):888-98
references.pmid: 19710487
references.citation: J Clin Invest. 2003 Jun;111(12):1887-95
references.pmid: 12813024
references.citation: J Exp Med. 2013 Oct 21;210(11):2181-90
references.pmid: 24101376
references.citation: Trends Immunol. 2011 Dec;32(12):603-11
references.pmid: 21958759
references.citation: Blood. 2010 Apr 15;115(15):3146-57
references.pmid: 20160165
references.citation: J Immunol. 2012 Aug 1;189(3):1123-7
references.pmid: 22753941
references.citation: Arthritis Rheum. 2010 Oct;62(10):3077-87
references.pmid: 20533545
references.citation: PLoS One. 2009;4(3):e5087
references.pmid: 19333372
references.citation: J Am Soc Nephrol. 2010 Sep;21(9):1587-96
references.pmid: 20634298
references.citation: Sci Transl Med. 2010 Oct 27;2(55):55ra78
references.pmid: 20980695
references.citation: Gastroenterology. 2012 Jul;143(1):62-69.e4
references.pmid: 22504093
references.citation: Blood. 2011 Dec 1;118(23):6107-14
references.pmid: 21926348
references.citation: J Immunol. 2012 Aug 1;189(3):1118-22
references.pmid: 22753931
references.citation: J Immunol. 2011 Sep 1;187(5):2824-33
references.pmid: 21821799
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Annu Rev Immunol. 2001;19:225-52
references.pmid: 11244036
references.citation: J Immunol. 2012 Feb 1;188(3):1206-12
references.pmid: 22184727