Projecting the global CD4 T cell differentiation patterns into the high-dimensional tSNE space again identified major alterations in the CD4 T cell response during COVID-19 infection compared to HDs and RDs (Fig. 3G). In COVID-19 infection, there was a notable increase in density in tSNE regions that mapped to expression of CD38, HLA-DR, PD1, CD39, KI67, and CD95 (Fig. 3G), similar to CD8 T cells. To gain more insight into these CD4 T cell changes, we again used a FlowSOM clustering approach (Fig. 3, H and I). This analysis identified an increase in Clusters 13 and 14 in COVID-19 patients compared to HD and RD that represent populations expressing HLA-DR, CD38, PD1, KI67 and CD95, as well as Cluster 15 that contained Tbet+CX3CR1+ “effector-like” CD4 T cells (Fig. 3, I and J, and fig. S3G). In contrast, this clustering approach identified reduction in CXCR5+ cTfh-like cells (Clusters 2, 3) in COVID-19 subjects compared to HD (Fig. 3, I and H). Taken together, this multidimensional analysis revealed distinct populations of activated/proliferating CD4 T cells that were enriched in COVID-19 patients.