Analysis of T-cell receptor variability in transplanted patients with acute graft-versus-host disease

Abstract

T lymphocytes play a pivotal role in graft-versus-host disease (GVHD) and largely contribute to the graft-versus-leukemia (GVL) effect. Most mature T lymphocytes specifically recognize antigens through the alpha/beta T-cell receptor (TCR). Each alpha/beta TCR chain includes a constant region and a variable region, the latter being encoded by V-J alpha or V-D-J beta rearranged gene segments. To better characterize T cells involved in GVHD, V alpha and V beta gene segment usage was analyzed, after cDNA amplification, in peripheral blood mononuclear cells (PBMC) and skin samples from three patients with grade II cutaneous GVHD. At time of GVHD diagnosis (days 11, 22, and 25), when first signs of engraftment were detectable, virtually all V alpha and V beta subfamilies were represented in PBMC RNAs of the three recipients. These results suggest that diversified TCR gene segment expression is observed early after allogenic bone marrow transplantation (alloBMT). Lymphocytes infiltrating GVHD skin also expressed a large series of V alpha and V beta subfamily specificities. However, analysis of the V alpha and V beta amplified products showed substantial differences between PBMC and the skin lymphocyte RNAs. These observations indicate that a large variety of T lymphocytes are present at the disease site, while some of them may be specifically amplified or decreased in response to minor histocompatibility antigens (miHA). Further characterization of the latter T-cell subpopulations should lead to a better understanding of human in vivo responses directed at miHA.

Pulmonary T cell repertoire in patients with graft-versus-host disease following blood and marrow transplantation

“…To our knowledge, this is the first study of the TCR AV and BV repertoire in the lungs of patients after BMT. This work extends the assessments of the T-cell reper-toire in peripheral blood [17][18][19][20] and skin [21] of BMT recipients, by testing both TCR AV and BV gene families, testing the lungs, and testing both CD4+ and CD8+ T-cell subpopulations. The analysis of TCR diversity is a powerful tool for monitoring immune reconstitution following BMT.…”

“…Unlike GVHD of the skin, liver, and intestine, which displays well-characterized histopathological alterations attributable in part to selective T-cellmediated epithelial destruction, a direct association between lung damage and allo-or autoreactivity in BMT recipients has been more obscure. Here, we demonstrate a restricted pattern of TCR junctional region lengths that indicates less polyclonality of T cells in the lungs of Patient Oligoclonal TCRV gene family detected Unfractionated BAL cells CD4 + BAL T cells CD8 + BAL T cells 1 AV15 BV9, 21 BV9, 21 BV17, 21 2 AV9, 11,14,18,26,27 AV11,12,14,26,27 AV1,4,9,11,13,18,19,26,29 BV16,23,24 BV16,21 BV9,16,21,23,24 3 AV4, 12,14,17,19,21,22 ND a ND BV4, 5S2, 9, 16, 25 6 AV8, 9,18,26 AV5,11 AV4,8,9,11,18,…”

“…A limited T-cell receptor (TCR) ␤ chain variability was demonstrated in peripheral blood of BMT recipients [17], particularly in the CD8+CD57+ T-cell subset (18). A restricted use of the TCR repertoire during acute GVHD was found in peripheral blood [19,20] and skin [21].…”

Narrowing of T‐cell receptor beta variable repertoire during symptomatic herpesvirus infection in transplant patients

“…7,8 Indeed, the diversity of the T-cell receptor (TCR) repertoire is often measured as an indication of the extent of immune reconstitution; it has been reported that nearly all allogeneic haematopoietic stem cell graft recipients experience TCR skewing. 9,10 There is an increasing focus on the correlation between immune system functionality and TCR diversity. 11 The ab-TCR consists of two chains, each comprising a variable (V), joining (J) and constant (C) gene, with the b-chain containing an additional diversity (D) gene.…”

“…This literature suggests that the ability of the patient to reconstitute their immune system post‐transplant is an important factor in determining the risk of developing virus infection and/or clinical disease 7 , 8 . Indeed, the diversity of the T‐cell receptor (TCR) repertoire is often measured as an indication of the extent of immune reconstitution; it has been reported that nearly all allogeneic haematopoietic stem cell graft recipients experience TCR skewing 9 , 10 . There is an increasing focus on the correlation between immune system functionality and TCR diversity 11 …”