T cell responses to human platelet antigen-1a involve a unique form of indirect allorecognition

• Published in: JCI insight 2016-09, Vol.1 (14), p.e86558-e86558
• Main Authors: Ahlen, Maria Therese, Husebekk, Anne, Killie, Ida Løken, Skogen, Bjørn, Stuge, Tor Brynjar
• Format: Article
• Language: English
• Subjects: Adult; Antigens, Human Platelet - immunology; Blood Platelets; Female; HLA-DRB3 Chains; Humans; Integrin beta3 - immunology; Pregnancy; T-Lymphocytes - immunology; Thrombocytopenia, Neonatal Alloimmune - immunology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.86558

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-related condition caused by maternal antibodies binding an alloantigen on fetal platelets. In most cases the alloantigen is formed by a single amino acid, integrin β3 Leu33, referred to as human platelet antigen-1a (HPA-1a). Production of anti-HPA-1a antibodies likely depends on CD4 T cells that recognize the same alloantigen in complex with the HLA-DRA/DRB3*01:01 molecule. While this complex is well characterized, T cell recognition of it is not. Here, to examine the nature of antigen recognition by HPA-1a-specific T cells, we assayed native and synthetic variants of the integrin β3 peptide antigen for binding to DRA/DRB3*01:01-positive antigen-presenting cells and for T cell activation. We found that HPA-1a-specific T cells recognize non-allogeneic integrin β3 residues anchored to DRA/DRB3*01:01 by the allogeneic Leu33, which itself is not directly recognized by these T cells. Furthermore, these T cell responses are diverse, with different T cells depending on different residues for recognition. This represents a unique form of indirect allorecognition in which a non-allogeneic peptide sequence becomes immunogenic by stable anchoring to MHC by an allogeneic residue.