CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

Abstract

High expression of CXCR5 is one of the defining hallmarks of T follicular helper cells (TFH), a CD4 Th cell subset that promotes germinal center reactions and the selection and affinity maturation of B cells. CXCR5 is also expressed on 20–25% of peripheral blood human central memory CD4 T cells (TCM), although the definitive function of these cells is not fully understood. The constitutive expression of CXCR5 on TFH cells and a fraction of circulating TCM suggests that CXCR5+ TCM may represent a specialized subset of memory-type TFH cells programmed for homing to follicles and providing B cell help. To verify this assumption, we analyzed this cell population and show its specialized function in supporting humoral immune responses. Compared with their CXCR5− TCM counterparts, CXCR5+ TCM expressed high levels of the chemokine CXCL13 and efficiently induced plasma cell differentiation and Ig secretion. We found that the distinct B cell helper qualities of CXCR5+ TCM were mainly due to high ICOS expression and pronounced responsiveness to ICOS ligand costimulation together with large IL-10 secretion. Furthermore, B cell helper attributes of CXCR5+ TCM were almost exclusively acquired on cognate interaction with B cells, but not with dendritic cells. This implies that a preferential recruitment of circulating CXCR5+ TCM to CXCL13-rich B cell follicles is required for the promotion of a quick and efficient protective secondary humoral immune response. Taken together, we propose that CXCR5+ TCM represent a distinct memory cell subset specialized in supporting Ab-mediated immune responses.

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…found that the number of antigen‐specific memory cells that expressed Tfh markers declined over time, suggesting that Tfh cells fail to differentiate into long‐lived memory cells 57. However, we and others have shown that both mouse and human CXCR5+ memory CD4 T‐cells provide rapid assistance to B‐cells upon reactivation 61, 62, 63, 64, 65, 66, 67, 68, 69. Importantly, Alexander et al .…”

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

“…T FH cells are present within and at the border of germinal centres (GC) in the secondary lymphoid organs. Their memory compartment circulates in peripheral blood (Chevalier et al, 2011;Morita et al, 2011). T FH cells were first described in human blood and tonsils as CD4 + T-cells expressing CXCR5, a chemokine receptor that is required for homing to the B-cell follicles (Förster et al, 1994;Breitfeld et al, 2000;Schaerli et al, 2000;Kim et al, 2001).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…They are found within the CXCR5 + subset of circulating CD4 + T cells,99, 159 although CXCR5 + can also be expressed on non‐Tfh cells. Precise definition of circulating memory Tfh cells is challenging, as resting memory Tfh cells in blood do not express Bcl6 or the high levels of PD‐1 and ICOS characteristic of GC Tfh cells and require re‐stimulation in order to mediate B‐cell helper activity 99, 159, 160, 162. A subpopulation of blood CXCR5 +  CD4 + T cells expresses PD‐1, although at lower levels than GC Tfh cells.…”