Organ-specific T cell receptor repertoire in target organs of murine graft-versus-host after transplantation across minor histocompatibility antigen barriers.
BACKGROUND
Minor histocompatibility antigens (miHags) are recognized by alloreactive cytotoxic donor T lymphocytes and trigger potent immune reactions such as graft-versus-host disease (GvHD) after major histocompatibility complex-matched transplantation. Our study focuses on tissue-specific T-cell responses to miHag-encoded peptides in GvHD target organs during the first 30 days in a murine transplant model.


METHODS
Complementarity determining region (CDR)3-size spectratyping was used to study T cell receptor (TCR) repertoires in recipient skin, liver, ileum, colon, spleen, and heart.


RESULTS
GvHD occurred as early as day 14 and was proven by histology in skin, liver, ileum, and colon. The heart was histologically not affected by GvHD but showed endomyocardial "quilty lesions." Two distinct patterns of TCR diversities could be identified. In skin, a restricted V beta usage in combination with all J beta segments contrasted with a complete V beta repertoire in intestinal organs combined with a restricted J beta usage. Interestingly, TCR repertoire in the heart was almost identical with intestinal CDR3-size patterns. Persisting clones were found in skin from day 9 to 30. In intestine and heart, identical sequences were obtained from several organs on day 14 and 21, but no persistence of CDR3 sequences could be observed.


CONCLUSIONS
These results suggest that in the skin a limited number of persisting T cell clones maintains GvHD, whereas in the intestine, temporary expansions of different clones may fuel the process of GvHD. Strategies that eliminate tissue-specific T cells on the basis of their activational status rather than their V beta expression but at the same time preserve a broad, overall TCR repertoire will help to increase the efficacy and safety of allogeneic stem cell transplantation.
Schilbach
Karin
K
Children's Hospital, Pediatric Stem Cell Transplant Program, University of Tübingen, Tübingen, Germany. knschilb@med.uni-tuebingen.de.
Schick
Judith
J
Fluhr
Herbert
H
Marquordt
Katja
K
Wehrmann
Manfred
M
Schütt
Burkhardt S
BS
Schlegel
Paul G
PG
Niethammer
Dietrich
D
Eyrich
Matthias
M
D000595:Amino Acid Sequence; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003106:Colon / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D007082:Ileum / Q000276:immunology; D008099:Liver / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology; D009928:Organ Specificity / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000276:immunology; D013154:Spleen / Q000276:immunology
D022801:Complementarity Determining Regions; D015778:Minor Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; C113249:T cell receptor peptide Vbeta8.1