CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Abstract

CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable Th1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

“…Both acute and chronic infection upregulated expression of genes related to the response to CD40 signaling within LZ GC B cells of cluster 4 and along both the branch leading to PC and MBC differentiation as well as the DZ re-entry branch (Figure S5B). This result was consistent with abundant Tfh during both LCMV Arm and clone 13 infections (Crawford et al, 2014;Fahey et al, 2011;Vella et al, 2017) and that CD40 agonism can drive both GC B cell DZ re-entry and terminal PC differentiation in vitro (Erickson et al, 2002;Foy et al, 1996). However, although the enrichment was similar between infections, the pattern of this CD40 help signal was distinct.…”

“…Pathway-2 5 level analysis revealed attenuated BCR signaling and increased inflammatory signaling at this decision point that favored GC exit over DZ re-entry. Dysregulation of humoral immunity during chronic infection has been linked to pre-GC B cell deletion (Fallet et al, 2016;Moseman et al, 2016;Sammicheli et al, 2016) and excess Tfh (Crawford et al, 2014;Fahey et al, 2011;Vella et al, 2017), but the B cell intrinsic events in the GC have not previously been defined. The single-cell nature of these studies now identify not only a role for altered GC biology, but also the specific decision point in the GC that is altered by chronic infection.…”

“…Signals from T follicular helper cells (Tfh) are critical during the cluster 4 testing phase and chronic LCMV infection leads to an abundance of Tfh (Crawford et al, 2014;Fahey et al, 2011;Vella et al, 2017). Indeed, several Tfh-derived signals were implicated in the scRNA-seq and bulk RNA-seq above.…”

CXCR5+CD4+ T cell subsets and their relationship to immune dysfunction in chronic hepatitis B‐associated liver cirrhosis

“…The upregulation of PLCs observed in d-HBC patients may explain the occurrence of hypergammaglobulinemia that was one of the hallmarks of CAID and reflects the abnormal systemic inflammation. 24 Our findings suggested that the unbalanced distribution of B cell subsets in patients with cirrhosis may contribute to CAID and play an important role in the progression of the disease. CXCR5 + CD4 + T cell subset is considered as a specialized T cell subset responsible for B cell regulation.…”

“…It indicates that the loss of MBs may explain the observed hyporesponsiveness to vaccine in cirrhosis patients. The upregulation of PLCs observed in d‐HBC patients may explain the occurrence of hypergammaglobulinemia that was one of the hallmarks of CAID and reflects the abnormal systemic inflammation . Our findings suggested that the unbalanced distribution of B cell subsets in patients with cirrhosis may contribute to CAID and play an important role in the progression of the disease.…”