BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ T cell responses to persistent antigen

Delineating the transcriptional landscape and clonal diversity of virus-specific CD4+ T cells during chronic viral infection

“…Interestingly, whereas ~11.5% of Slamf6-hi cells were found to reside along the Tfh branch, ~42.6% of cells from the pre-Tfh cluster were found along this branch ( Figure 3A–B ), further supporting that cells from the pre-Tfh cluster may be en route toward developing along a Tfh differentiation pathway. Notably, findings from our Monocle trajectory analysis closely align with recent reports demonstrating that memory-like CD4 + T cells are capable of giving rise to both Tfh and Th1 effector cells subsets following adoptive transfer (possibly through an intermediate state), whereas Th1 and Tfh cells do not readily interconvert between one another during chronic viral infection ( Xia et al, 2022 ; Zander et al, 2022 ).…”

“…Consistent with this observation, clusters 0 and 1 also displayed increased memory T cell module scores ( Figure 1I ) and relatively lower Th1 and Tfh module scores, although cluster 1 did display the third highest Tfh module score behind the GC Tfh2 and Tfh1 clusters. Together, these data suggest that cells from clusters 0 to 1 likely fall within the Slamf6 + T memory-like cell subset that we and others have recently demonstrated develops during chronic LCMV infection, of which largely remains in a quiescent-like state, yet does display some developmental plasticity ( Xia et al, 2022 ; Zander et al, 2022 ). Interestingly, compared to cluster 0, cluster 1 did display increased expression of Tnfrsf4 , Batf , Il1r2 , and Cd83 ( Figure 1E , Figure 1—figure supplement 1A ), which were also highly expressed in the Tfh1 population, possibly indicating that cells from cluster 1 are in a more activated state.…”

“…Interestingly, compared to cluster 0, cluster 1 did display increased expression of Tnfrsf4 , Batf , Il1r2 , and Cd83 ( Figure 1E , Figure 1—figure supplement 1A ), which were also highly expressed in the Tfh1 population, possibly indicating that cells from cluster 1 are in a more activated state. Given that cluster 1 had an increased Tfh module score relative to cluster 0, coupled with recent reports that some memory-like CD4 + T cells can give rise to Tfh cells ( Xia et al, 2022 ; Zander et al, 2022 ), we elected to refer to clusters 0 and 1 as Slamf6-hi and pre-Tfh cells respectively.…”

“…This shift in CD4 + T cell differentiation is thought to be important to limit Th1-mediated immunopathology ( Penaloza-MacMaster et al, 2015 ), while at the same time promote Tfh-mediated antibody responses that are required for viral clearance from the periphery ( Fahey et al, 2011 ; Harker et al, 2011 ; Cook et al, 2015 ; Greczmiel et al, 2017 ). Notably, recent work in the field has further demonstrated that in addition to the anticipated Th1 and Tfh populations that form during chronic viral infection, a previously unrecognized memory-like CD4 + T cell subset also develops, and this subset bears a transcriptional program similar to that of Tcmp cells from acute infection, as evident by its high expression of Tcf7 , Ccr7 , Il7r , and Bcl2 ( Snell et al, 2021 ; Andreatta et al, 2022 ; Xia et al, 2022 ; Zander et al, 2022 ). Moreover, memory-like CD4 + T cells were found to display an augmented capacity to accumulate during persistent infection, and they also exhibited the propensity to give rise to either Th1 or Tfh cells, indicating that this subset displays some developmental plasticity ( Xia et al, 2022 ; Zander et al, 2022 ).…”

“…Notably, recent work in the field has further demonstrated that in addition to the anticipated Th1 and Tfh populations that form during chronic viral infection, a previously unrecognized memory-like CD4 + T cell subset also develops, and this subset bears a transcriptional program similar to that of Tcmp cells from acute infection, as evident by its high expression of Tcf7 , Ccr7 , Il7r , and Bcl2 ( Snell et al, 2021 ; Andreatta et al, 2022 ; Xia et al, 2022 ; Zander et al, 2022 ). Moreover, memory-like CD4 + T cells were found to display an augmented capacity to accumulate during persistent infection, and they also exhibited the propensity to give rise to either Th1 or Tfh cells, indicating that this subset displays some developmental plasticity ( Xia et al, 2022 ; Zander et al, 2022 ). Thus, CD4 + T cells responding to chronic viral infection are also capable of exhibiting memory-like properties, even in the presence of ongoing viral replication.…”