Convergent clonal selection of donor- and recipient-derived CMV-specific T cells in hematopoietic stem cell transplant patients

Competition between antigen-specific T cells for peptide:MHC complexes shapes the ensuing T cell response. Mouse model studies provided compelling evidence that competition is a highly effective mechanism controlling the activation of naive T cells. However, assessing the effect of T cell competition in the context of a human infection requires defined pathogen kinetics and trackable naive and memory T cell populations of defined specificity. A unique cohort of nonmyeloablative hematopoietic stem cell transplant patients allowed us to assess T cell competition in response to cytomegalovirus (CMV) reactivation, which was documented with detailed virology data. In our cohort, hematopoietic stem cell transplant donors and recipients were CMV seronegative and positive, respectively, thus providing genetically distinct memory and naive T cell populations. We used single-cell transcriptomics to track donor versus recipient-derived T cell clones over the course of 90 d. We found that donor-derived T cell clones proliferated and expanded substantially following CMV reactivation. However, for immunodominant CMV epitopes, recipient-derived memory T cells remained the overall dominant population. This dominance was maintained despite more robust clonal expansion of donorderived T cells in response to CMV reactivation. Interestingly, the donor-derived T cells that were recruited into these immunodominant memory populations shared strikingly similar TCR properties with the recipient-derived memory T cells. This selective recruitment of identical and nearly identical clones from the naive into the immunodominant memory T cell pool suggests that competition is in place but does not interfere with rejuvenating a memory T cell population. Instead, it results in selection of convergent clones to the memory T cell pool.

Automated summary

Competition between antigen-specific T cells for peptide:MHC complexes shapes the ensuing T cell response. This study found that in human transplant patients, competition between donor and recipient cells results in selective clonal proliferation and expansion of memory T cell populations, with different clones entering the immunodominant memory T cell pool.