Hobit and Blimp-1 instruct the differentiation of iNKT cells into resident-phenotype lymphocytes after lineage commitment

iNKT cells are CD1d-restricted T cells that play a pro-inflammatory or regulatory role in infectious and autoimmune diseases. Thymic precursors of iNKT cells eventually develop into distinct iNKT1, iNKT2, and iNKT17 lineages in the periphery. It remains unclear whether iNKT cells retain developmental potential after lineage commitment. iNKT cells acquire a similar phenotype as tissue-resident memory T cells, suggesting that they also differentiate along a trajectory that enables them to persist in peripheral tissues. Here, we addressed whether lineage commitment and memory differentiation are parallel or sequential developmental programs of iNKT cells. We defined three subsets of peripheral iNKT cells using CD62L and CD69 expression that separate central, effector, and resident memory phenotype cells. The majority of iNKT1 cells displayed a resident phenotype in contrast to iNKT2 and iNKT17 cells. The transcription factor Hobit, which is upregulated in iNKT cells, plays an essential role in their development together with its homolog Blimp-1. Hobit and Blimp-1 instructed the differentiation of central memory iNKT cells into resident memory iNKT cells, but did not impact commitment into iNKT1, iNKT2, or iNKT17 lineages. Thus, we conclude that memory differentiation and the establishment of residency occur after lineage commitment through a Hobit and Blimp-1-driven transcriptional program

Parallel detection of SARS-CoV-2 epitopes reveals dynamic immunodominance profiles of CD8+ T memory cells in convalescent COVID-19 donors

Objectives: High-magnitude CD8+ T cell responses are associated with mild COVID-19 disease; however, the underlying characteristics that define CD8+ T cell-mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope-specific CD8+ T cells remain largely unexplored and are essential for the development of next-generation broad-protective vaccines. This study identified a broad spectrum of conserved SARS-CoV-2 CD8+ T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS-CoV-2 infection. Methods: CD8+ T cells from 51 convalescent COVID-19 donors were analysed for their ability to recognise 133 predicted and previously described SARS-CoV-2-derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in-depth ex vivo profiling of CD8+ T cell responses at quantitative and phenotypic levels. Results: A comprehensive panel of 49 mostly conserved SARS-CoV-2-specific CD8+ T cell epitopes, including five newly identified low-magnitude epitopes, was established. We confirmed the immunodominance of HLA-A*01:01/ORF1ab1637–1646 and B*07:02/N105–113 and identified B*35:01/N325–333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N361–369 and A*02:01/S269–277, depended on the donors' HLA-I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID-19 donors. Conclusion: SARS-CoV-2 infection induces a predominant CD8+ T memory response directed against a broad spectrum of conserved SARS-CoV-2 epitopes, which likely contributes to long-term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross-reactive immune response, which could aid future vaccine strategies