Divergent Clonal Differentiation Trajectories Establish CD8 ⁺ Memory T Cell Heterogeneity During Acute Viral Infections in Humans

Abstract

CD8⁺ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8⁺ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked hundreds of CD8⁺ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute phase of the response are detected as circulating memory T cells later, indicative of clonal selection shaping the memory repertoire. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient from stem cell memory to terminally differentiated effector memory fates. Reactivation of single memory CD8⁺ T cell clones revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.

Keywords: Human CD8+ T cell memory, Yellow fever virus, differentiation, Clones, single cell RNAseq, Vaccines