Antigen-Specificity of T Cell Infiltrates in Biopsies With T Cell-Mediated Rejection and BK Polyomavirus Viremia: Analysis by Next Generation Sequencing.
This study interrogates the antigen-specificity of inflammatory infiltrates in renal biopsies with BK polyomavirus (BKPyV) viremia (BKPyVM) with or without allograft nephropathy (BKPyVN). Peripheral blood mononuclear cells (PBMC) from five healthy HLA-A0101 subjects were stimulated by peptides derived from the BKPYV proteome or polymorphic regions of HLA. Next generation sequencing of the T cell-receptor complementary DNA was performed on peptide-stimulated PBMC and 23 biopsies with T cell-mediated rejection (TCMR) or BKPyVN. Biopsies from patients with BKPyVM or BKVPyVN contained 7.7732 times more alloreactive than virus-reactive clones. Biopsies with TCMR also contained BKPyV-specific clones, presumably a manifestation of heterologous immunity. The mean cumulative T cell clonal frequency was 0.1378 for alloreactive clones and 0.0375 for BKPyV-reactive clones. Samples with BKPyVN and TCMR clustered separately in dendrograms of V-family and J-gene utilization patterns. Dendrograms also revealed that V-gene, J-gene, and D-gene usage patterns were a function of HLA type. In conclusion, biopsies with BKPyVN contain abundant allospecific clones that exceed the number of virus-reactive clones. The T cell component of tissue injury in viral nephropathy appears to be mediated primarily by an "innocent bystander" mechanism in which the principal element is secondary T cell influx triggered by both antiviral and anti-HLA immunity.
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
G
G
Zeng
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
Y
Y
Huang
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
Y
Y
Huang
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
Z
Z
Lyu
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
D
D
Lesniak
Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA. randhawapa@upmc.edu.
P
P
Randhawa
D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001739:BK Virus / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000276:immunology* / Q000821:virology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014412:Tumor Virus Infections / Q000276:immunology* / Q000821:virology; D055815:Young Adult
D011948:Receptors, Antigen, T-Cell
basic (laboratory) research/science; genetics; infectious disease; kidney transplantation/nephrology; rejection; rejection: T cell-mediated (TCMR); translational research/science