Extensive clonal expansion of T lymphocytes causes contracted diversity of complementarity-determining region 3 and skewed T cell receptor repertoires after allogeneic hematopoietic cell transplantation

Abstract

Summary:We previously described skewed repertoires of the T cell receptor-␤ chain variable region (TCRBV) and the TCR-␣ chain variable region (TCRAV) soon after allogeneic hematopoietic cell transplantation. To determine the characteristics of skewed TCRBV after transplantation, we examined the clonality of T lymphocytes carrying skewed TCRBV subfamilies and determined the CDR3 sequences of expanded T cell clones. In all 11 recipients examined, TCR repertoires were skewed, with an increase of certain TCRBV subfamilies that differed among individuals. In nine of 11 patients, clonal/oligoclonal T cell expansion was observed, although the expanded T cells were not necessarily oligoclonal. The extent of expansion after transplantation appeared to predict clonality. The arginine (R)-X-X-glycine (G) sequence was identified in clonally expanded T cells from four of five recipients examined, and glutamic acid (E), aspartic acid (D) and alanine (A) were frequently inserted between R and G. These results suggest that T lymphocyte expansion may result from the response to antigens widely existing in humans, and that the extensive clonal expansion of a limited number of T cells leads to contracted CDR3 diversity and post-transplant skewed TCR repertoires. Bone Marrow Transplantation (2001) 27, 607-614. Keywords: T cell clonality; CDR3; allogeneic hematopoietic cell transplantationWe have found skewed TCRAV and TCRBV repertoires soon after allogeneic hematopoietic cell transplantation in virtually all tested recipients. 1 Furthermore, we demonstrated that reconstitution of the ␣␤ T cell, but not the ␥␦ T cell repertoire was incomplete for at least 2 months after transplantation, and that the delayed reconstitution of TCR repertoire diversity was more profound in immunocompro- mised hosts. 2,3 We also found that TCR usage appears to be limited, and that amino acid sequences frequently contain an arginine residue followed by acidic amino acid residues in the complementarity-determining region 3 (CDR3) of TCR-␤ chains containing BV24S1, suggesting that skewing of the TCRAV and TCRBV repertoires is antigen-driven. 1 These features of post-transplant T cell regeneration are similar to those during extrathymic differentiation of T cell progenitors and peripheral expansion of mature T cell populations, which have been demonstrated by murine bone marrow transplantation studies. 4 Extrathymic differentiation of T cell progeny in bone marrow generates TCR␥␦ ϩ and CD4 Ϫ CD8 Ϫ TCR␣␤ ϩ T cells. 5,6 Peripheral expansion of mature T lymphocytes is driven by the antigenic milieu of the host 7,8 and gives rise to substantial numbers of TCR␣␤ ϩ CD4 ϩ and TCR␣␤ ϩ CD8 ϩ T cells. 5,9 However, an infusion of a limited number of T cells into athymic mice results in skewed TCR repertoires. 5 Clonal expansion of T lymphocytes is the principal mechanism of antigen-specific immune responses. 10,11 The CDR3 regions of TCRBV and TCRAV make the principal contact with an antigenic peptide that is bound to the major histocompatibility complex (MHC) and the...

Distinct TCRAV and TCRBV repertoire and CDR3 sequence of T lymphocytes clonally expanded in blood and GVHD lesions after human allogeneic bone marrow transplantation

“…5 This results from the extensive clonal expansion of a limited number of T cells in the graft. 6 Skewed TCR repertoires accompany accumulation of the CD28 Ϫ fraction in both CD4 + and CD8 + T cells. 7,8 Since accumulating evidence indicates an association between the loss of CD28 expression and T lymphocyte aging, 9,10 posttransplant skewing of the TCR repertoires probably results from chronic antigen stimulation in vivo.…”

“…5,6 To address whether or not the clonally expanded T cells in circulating blood recognize the same antigen as those expanded in GVHD lesions, we compared the usage of TCRAV and TCRBV subfamilies and the CDR3 sequences of clonally expanded T cells from blood and tissues. Since expanded T cells in the blood were not necessarily clonal/oligoclonal, 6 clonality was first determined by TCRBV-CDR3 size spectratyping (Figure 4), then the CDR3 sequences of clonally expanded T cells were analyzed. Table 6 shows that usage of the TCRBV subfamily by T cells clonally expanded in the blood and the structure of CDR3 of those lymphocytes differed from those of T lymphocytes expanded in GVHD tissues.…”

The presence and longevity of peripherally expanded donor-derived TCRαβ+ mature T lymphocyte clones after allogeneic bone marrow transplantation for adult myeloid leukemias

“…However, direct evidence of the antigens that are responsible for maintaining the clonal expansion of donorderived mature TCRab+ T lymphocytes for many years after transplant remains elusive. We reported that recipients of allogeneic bone marrow grafts have clonally expanded TCRab+ T lymphocytes soon after transplantation, leading to a skew of TCR repertoires, 3,6 and that the usage of TCRAV and TCRBV by the clonally expanded T lymphocytes and their CDR3 sequences differ between the GVHD and blood. 40 Thus, the clonal expansion of T cells in blood does not necessarily mean allogeneic T-cell responses.…”

“…4 Moreover, we found that a skew of the T-cell repertoire can be caused by the clonal expansion of TCRab+CD8+CD28À T cells, 5 and that consensus motifs of amino acids are observed in the complementarity-determining region 3 (CDR3) of clonally expanded T cells among distinct recipients. 6 Animal studies have shown that injecting athymic mice with a limited number of mature T lymphocytes skews the T-cell repertoire, the regeneration of which is affected by the host antigenic milieu. 7 Therefore, the above features of T-cell repertoire reconstitution suggest that the peripheral expansion of donor-derived mature T lymphocytes plays a certain role in T-cell regeneration after human HSCT.…”

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“…When immunodeficient animals, such as athymic (lacking thymus) mutants and in several types of knock-out animals are transplanted with a sub-optimal variety of syngenic T lymphocytes, these lymphocytes overexpand and may create fatal pathogenic situations 52,53 . A very high synthesis of IgE is included as an unexplained component of these expansions 54 .…”