Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras

Abstract

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

“…Our data show that the recovery of the peripheral T-cell compartment after HSC GT for ADA-SCID is driven by both naive and memory cells, to an extent comparable to what is observed in our age-matched cohort of patients undergoing allogeneic BMT and in previous reports in pediatric and adult BMT recipients. [13][14][15] Our cohort of pediatric BMT patients was heterogeneous and included only a minority of patients with ADA-SCID. Nevertheless, we did not find statistically significant differences within this cohort by comparing the absolute number of lymphocytes or T-cell subsets counts with respect to conditioning or diagnosis (data not shown; Fig E2).…”

“…12 After BMT, the reconstitution of the peripheral T cells is mainly driven by memory cells, particularly at early follow-up, in both pediatric and adult recipients. [13][14][15] There is limited information on the relative contribution of the different T-cell subsets and the various mechanisms of differentiation during the T-cell pool reconstitution after GT treatment.…”

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…Evaluation of T cell reconstitution should include enumeration of T cell populations (i.e., CD3, CD4 and CD8 T cell counts), naïve (CD4+CD45RA+) T cells and/or recent thymic emigrants (CD4+/CD45RA+/CD31+), and T cell function via proliferation to mitogens and/or anti-CD3. T cell receptor excision circle (TREC) counts are an indicator of thymic output, and robust TREC counts have been associated with higher CD3 and naïve T cell counts, T cell proliferation to mitogen, and T cell receptor diversity in some studies 12,20 . The TREC count early after HCT has also been proposed as a biomarker for long-term T cell reconstitution 21 .…”

“…The TREC count early after HCT has also been proposed as a biomarker for long-term T cell reconstitution 21 . T cell spectratyping is recommended to evaluate diversity of the T cell repertoire 20 , where a skewed repertoire may be associated with a high risk of infection and autoimmunity. A restricted Vβ T-cell receptor repertoire was also recently shown to be associated with need for second transplant and death 8 .…”

“…T cell reconstitution is the primary objective of transplantation for all forms of SCID, and normal T cell function is generally achieved between 4 to 9 months after HCT [17][18][19][20] . B-SCID genotypes, active infection at time of HCT, and graft-versus-host disease (GVHD) are all associated with poor T cell recovery 3,7,8,17 .…”