Delineation of naïve CD8+ T cell loss and reconstitution following exposure to sublethal whole-boy irradiation

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Abstract While the immunosuppressive effect of ionizing radiation (IR) is commonly used as a conditioning regimen of hematopoietic stem cell transplants, delayed immune reconstitution, mainly lymphocytes, remains a leading cause of morbidity and mortality. We have previously shown that memory CD8+ T (TMEM) lymphocytes, potent mediators of anti-tumor and intracellular re-infections, are permanently lost and exhibit subpar functionality long after sublethal whole-body irradiation (WBI). However, the long-term impact of WBI on naïve CD8+ T (TN) cells, a key component of immune response to new intracellular pathogens, remains poorly understood. Using P14 LCMV immune chimeric mice, we observed that although TN cells are more susceptible to radiation-induced cell loss than bona-fide TMEM cells, the number of TN cells gradually recovered in a thymus-dependent manner. Profiling the T cell receptor (TCR) beta-chain repertoire within total TN cells revealed altered TCR clonotype composition and diversity in lymphoreplete irradiated hosts. Additionally, the numerical recovery of TN cells was concomitant with an increased representation of virtual memory phenotype (CD11ahi, CD49dlo, CD62Lhi) in total and GAP5041-48, B8R20-27, and GP33-41 epitope-specific CD8+ T cells. Together, these data demonstrate lasting numerical and phenotypical changes to the TN compartment, which may influence the breadth of primary immune responses to newly encountered antigens or infections.

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