Clonal CD8+ T Cell Persistence and Variable Gene Usage Bias in a Human Transplanted Hand.
Immune prophylaxis and treatment of transplanted tissue rejection act indiscriminately, risking serious infections and malignancies. Although animal data suggest that cellular immune responses causing rejection may be rather narrow and predictable based on genetic background, there are only limited data regarding the clonal breadth of anti-donor responses in humans after allogeneic organ transplantation. We evaluated the graft-infiltrating CD8+ T lymphocytes in skin punch biopsies of a transplanted hand over 178 days. Profiling of T cell receptor (TCR) variable gene usage and size distribution of the infiltrating cells revealed marked skewing of the TCR repertoire indicating oligoclonality, but relatively normal distributions in the blood. Although sampling limitation prevented complete assessment of the TCR repertoire, sequencing further identified 11 TCR clonal expansions that persisted through varying degrees of clinical rejection and immunosuppressive therapy. These 11 clones were limited to three TCR beta chain variable (BV) gene families. Overall, these data indicate significant oligoclonality and likely restricted BV gene usage of alloreactive CD8+ T lymphocytes, and suggest that changes in rejection status are more due to varying regulation of their activity or number rather than shifts in the clonal populations in the transplanted organ. Given that controlled animal models produce predictable BV usage in T lymphocytes mediating rejection, understanding the determinants of TCR gene usage associated with rejection in humans may have application in specifically targeted immunotherapy.
Division of Infectious Diseases, Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Microbiology, Immunology, and Molecular Genetics, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Joseph Y
JY
Kim
Division of Infectious Diseases, Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Arumugam
A
Balamurugan
Department of Orthopaedic Surgery, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Kodi
K
Azari
Division of Infectious Diseases, Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Christian
C
Hofmann
Division of Infectious Diseases, Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Hwee L
HL
Ng
Department of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; UCLA Immunogenetics Center, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Elaine F
EF
Reed
Division of Gastroenterology, Department of Pediatrics, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Suzanne
S
McDiarmid
Division of Infectious Diseases, Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Microbiology, Immunology, and Molecular Genetics, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Otto O
OO
Yang
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D019672:Genes, T-Cell Receptor; D014644:Genetic Variation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology; D063987:Hand Transplantation / Q000009:adverse effects; D006801:Humans; D018448:Models, Immunological; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000276:immunology / Q000473:pathology; D013997:Time Factors