Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help

Abstract

IntroductionTo effectively fight invading pathogens, mammals have developed a repertoire of adaptive immune mechanisms that include the production of high-affinity antibodies. A critical event in the initiation of the humoral immune response reflects the timely interaction of B and T cells specific for the same antigen. The border between T-cell zone and B cell-rich follicles in lymph nodes (LNs) and the white pulp of the spleen are commonly considered as the place where the initial interaction between antigen-specific T and B cells occurs. 1 After receiving signals from activated CD4 T cells via the interaction of CD40/CD40L and further costimulatory molecules, some B cells differentiate into plasmablasts, which migrate to the red pulp of the spleen to become short-lived plasma cells secreting low-affinity antibodies. Following the interaction with T cells, other B cells migrate into the B follicle, start to proliferate, and form germinal centers (GCs). 2 It is widely accepted that isotype switching and affinity maturation of B cells depend on CD4 T helper cells. Some of these might also migrate into the follicle and GC. Thus, the coordinated migration of B and T cells appears to represent a decisive event that allows lymphocytes to make contact with each other.Ample evidence indicates that the migration of lymphocytes into secondary lymphoid organs is controlled by a chemokinedriven process. During the last decade several chemokines have been identified that are expressed in lymphoid organs, which guide resting or activated cells to their point of destination. Naive T cells express the chemokine receptor CCR7, which allows recruitment of these cells into T-cell areas of LNs or to the splenic white pulp through interaction with its ligands CCL19 and CCL21. These chemokines are expressed at specialized high endothelial venules (HEVs) in LNs and by lymphoid and nonlymphoid cells in the T-cell area of LNs and spleen. 3,4 In addition to CXCR4, CCR6, and CXCR5, B cells also express CCR7 to be able to enter lymphoid organs efficiently. Once entered these cells require CXCR5 to follow a chemokine gradient build up by CXL13 that is constitutively expressed on stromal cells in the follicles. 5 The differential localization of B cells during the different phases of an antigenspecific immune response is facilitated by the balanced responsiveness of these cells toward the chemokines CXCL13 and CCL19/CCL21. 6 In contrast to the situation described for B cells, less is known about molecular mechanisms that guide the small subpopulation of CD4 ϩ helper T cells into the B-cell follicle. These cells lack a distinct T H 1 or T H 2 cytokine expression profile but express costimulatory molecules such as inducible costimulator (ICOS) and CD40L and induce B cells to produce IgG and IgA in vitro. 7,8 Based on this ability and due to the fact that these cells express CXCR5, a chemokine receptor known to be essential for the localization of B cells to the follicle, we and others termed these T cells "follicular B helper T cells" (T FH ...

Abundance of follicular helper T cells in Peyer's patches is modulated by CD155

“…Although downregulation of CCR7 is mandatory to accomplish this, CXCR5 expression is not sufficient to warrant localization of T FH cells to the GC. This is illustrated by the finding that CXCR5-deficient T FH cells fail to enter the B-cell follicle, yet are present in the GC that is embedded inside the follicle [30,36]. However, the frequency of CXCR5-deficient T FH cells in GC was observed to be reduced [36].…”

“…However, the frequency of CXCR5-deficient T FH cells in GC was observed to be reduced [36]. Remarkably, CXCR5 deficiency does not affect the induction of IgM production [37] whereas the ability to mount an isotype-switched antibody response is impaired [30]. These observations are reminiscent of those elicited by CD155 deficiency except that in the latter case reduced T FH -cell frequencies and impairment of the isotype-switched antibody response restricts to the mucosal immune system of the gastrointestinal tract.…”

“…To reveal CCR7 expression, additionally, an ELC-hIgG recombinant protein was used as described earlier [30].…”

“…T FH cells play an important role for the establishment and maintenance of the GC reaction [28]. Although the pathways inducing their generation remain obscure, it was demonstrated that a tightly controlled counter-balance between the expression of the T area directing chemokine receptor CCR7 and the B follicle homing receptor CXCR5 navigates these activated cells into or close to the B-cell-rich zone where they assist in priming B cells [29,30]. Later on, T FH cells co-locate to the GC where they provide B-cell blasts with signals (e.g.…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…The binding of CXCR5 on T FH cells with its cognate ligand, CXCL-13, in GC facilitates the migration of T FH cells to B-cell follicles for their interaction with B cells. 13,14 Upon T FH -cell activation, PD-1 induces an inhibitory signal to T FH cells, whereas ICOS functions as a costimulatory molecule, thus determining the outcome of the T FH cell-mediated B-cell response. 15,16 Furthermore, CD40L, a member of the tumor necrosis factor family, is expressed on activated T FH cells, and its interaction with CD40 on B cells is crucial for immunoglobulin isotype switching.…”