Allorecognition of HLA-DP by CD4+ T cells is affected by polymorphism in its alpha chain.
Alloreactivity to HLA-DP molecules, class II heterodimers of an oligomorphic alpha and a polymorphic beta chain, is increasingly being studied due to its relevance in clinical transplantation. We hypothesized that not only polymorphisms in the peptide binding groove encoded by exon 2 of HLA-DPB1, but also in other regions of the molecule and the alpha chain, could play a role in CD4+ T cell allorecognition. To test this possibility, we comparatively investigated CD4+ T cell allorecognition, measured by upregulation of the activation marker CD137, against HLA-DPB1*13:01, *05:01, *03:01, *17:01 or their allele counter parts DPB1*107:01, *135:01, *104:01, *131:01, with identical exon 2 sequences but polymorphism in exons 1, 3 or 4, in the context of different HLA-DPA1 (DPA1) polymorphisms (DPA1*01:03 and *02:01). No significant differences in CD4+ T cell allorecognition levels could be demonstrated for any of the beyond exon 2 DPB1 variants studied. Interestingly, however, the mean fold change in CD4+ CD137+ cells was significantly higher when the target shared at least one DPA1 allele with the allogeneic stimulator, compared to a distinct DPA1 background (1.65 vs 0.23, P<0.005). Structural homology modeling suggested specific amino acid residues in the alpha chain, in particular position 31, to impact CD4+ T cell allorecognition of HLA-DP. Our data argue against a significant role of beyond exon 2 DPB1 polymorphisms for T cell alloreactivity, but show relevance of DPA1 polymorphism in this mechanism. These new findings impact HLA matching strategies in unrelated stem cell transplantation.
Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Nina
N
Lauterbach
Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
Pietro
P
Crivello
Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Lotte
L
Wieten
Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
Laura
L
Zito
Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Mathijs
M
Groeneweg
Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Christina E M
CE
Voorter
Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Present adress: Institute for Experimental and Cellular Therapy, University of Essen, Germany.
Katharina
K
Fleischhauer
Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: m.tilanus@mumc.nl.
Marcel G J
MG
Tilanus
D000483:Alleles; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006682:HLA-DP Antigens / Q000145:classification / Q000235:genetics / Q000276:immunology*; D059867:HLA-DP alpha-Chains / Q000145:classification / Q000235:genetics / Q000276:immunology*; D059868:HLA-DP beta-Chains / Q000145:classification / Q000235:genetics / Q000276:immunology; D006648:Histocompatibility / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000276:immunology*; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D006682:HLA-DP Antigens; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen
Allorecognition; HLA-DPA1; HLA-DPB1