T cell repertoire following autologous stem cell transplantation for multiple sclerosis

Abstract

Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCRβ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies.

Trial registration: ClinicalTrials.gov NCT00288626.

Figure 1. Proportional analysis of individual T cell clonal frequencies after HSCT.

(A) Model used for classification of clonal frequency, and application of this model to a representative CD4⁺ and CD8⁺ repertoire (see text for further details). (B) Proportion of clonal classes for each participant, as defined in A, among CD4⁺ and CD8⁺ cells at baseline and at month 12.

Figure 2. Longitudinal evaluation of T cell clones after HSCT.

(A) Evolution of individual clonal frequencies. “New” refers to clones not present before treatment; “expanded” clones have increased from 1+ or 2+ before treatment (see Figure 1A) to 3+ or 4+; and “persistent” clones have not changed their classification frequency. (B) Proportional representation of the clones that were found to be the 100 most frequent at 2 months after transplant in CD4⁺ (top) and CD8⁺ (bottom) T cells.

Figure 3. Relationship between TCR diversity and response to HSCT.

TCR diversity at 2 months after HSCT in CD4⁺ (top) and CD8⁺ (bottom) T cells divided by patients who remained stable (responder, n = 20 at baseline; and n = 19 at 2 months, as no sample was available for one patient) and who relapsed (non-responder, n = 4). The box represents the interquartile range, with the line being the median and the whiskers being 1.5× the interquartile range.