ICOS+CD38+ cTfh in peripheral blood and thoracic duct lymph.

Abstract

Abstract T follicular helper cells provide essential B cell help within the germinal center (GC), and these cells have been shown to populate the follicular mantel once the GC reaction is complete. The significance and ontology of circulating Tfh (cTfh) is less clear. Studies in humans have suggested subsets of cTfh that correlate with humoral responses in chronic infection (HIV, malaria) and in response to acute challenge (influenza vaccination). We have previously described a subset of CXCR5+PD1+ cTfh that expresses both ICOS and CD38. This population was significantly increased 7 days after influenza vaccination as well as in patients infected with HIV. Single cell transcriptional analysis of the ICOS+CD38+ cTfh after influenza vaccination demonstrated more frequent expression of the GC Tfh transcripts CMAF, BCL6, and CD200 than was found in the ICOS−CD38− cTfh, and bulk transcriptional analysis indicated higher expression of IL-21. These data suggested that ICOS and CD38 mark the rare population of cTfh that are more recent émigrés from the lymph nodes. To evaluate this possibility, we analyzed Tfh in an immune compartment that is more proximal to the lymph nodes than peripheral blood: thoracic duct lymph (TDL). As expected, TDL Tfh had a higher frequency of ICOS+CD38+ cells than cTfh in matched peripheral blood. In addition, TDL had a population of CXCR5+PD1bright Tfh, previously only identified in lymphoid tissues. CXCR5+PD1bright Tfh in the TDL had a significantly increased frequency of ICOS+CD38+ cells. These data provide a critical missing link in the understanding of cTfh and suggest that the ICOS+CD38+ cTfh subset warrants further exploration as peripheral surrogates of the active immune responses within secondary lymphoid tissues.