Crucial Roles of Interleukin-7 in the Development of T Follicular Helper Cells and in the Induction of Humoral Immunity

Abstract

Interleukin-7 (IL-7) is a heavily glycosylated cytokine with a molecular mass of 25 kDa, and it is a member of the common ␥-chain receptor (CD132) cytokine family. IL-7 is secreted mainly by nonhematopoietic cells, such as thymic and intestinal epithelial cells, bone marrow stromal cells, keratinocytes, and reticular cells (1, 2). The receptor for IL-7, comprised of IL-7 receptor alpha (IL-7R␣; CD127) and the common ␥ chain, is expressed on various immune cells, including immature B cells, early thymocyte progenitors, and most mature T lymphocytes. IL-7 plays a role in the development of T cells, B cells, certain subsets of NK cells, and dendritic cells (DCs), as well as in the homeostasis of naive and memory T cells. In addition, IL-7 is important for ␥␦ T cell proliferation and NKT cell maintenance. However, the role of IL-7 in the differentiation of T follicular helper (Tfh) cells and the induction of humoral immunity remains unclear.Tfh cells are the unique CD4 ϩ T helper (Th) cells that provide cognate help to B cells to induce high-affinity antibody production in germinal centers (GCs) (3). GCs are specialized structures that develop within B cell follicles of secondary lymphoid tissues. GCs support intense B cell clonal expansion, somatic hypermutation, selection of high-affinity B cells, and class switching of immunoglobulin genes. These B cells ultimately are differentiated into both memory B cells and long-lived plasma cells that secrete high-affinity antibodies (2, 4).The differentiation of Tfh cells depends on the expression of a master transcriptional repressor, Bcl-6, which inhibits non-Tfh lineage differentiation (Th1, Th2, and Th17) by repressing Blimp-1 (5). Tfh cells express CXCR5 and a number of costimulatory molecules, such as ICOS and PD-1 (6). In addition, IL-6 and IL-21 have been shown to be important soluble regulators for the differentiation of Tfh cells (7-9). Recently, IL-27 was shown to increase the Tfh cell differentiation by upregulating IL-21 production (10). However, there have been conflicting reports that the absence of either IL-6 or IL-21 exhibits significant, moderate, or minimal effects on Tfh cell differentiation. The absence of both cytokines resulted in a more significant decrease in Tfh cell generation than each cytokine alone in vivo (11), indicating that IL-6 and IL-21 have redundant and/or additive functions in Tfh differentiation. It remains to be determined whether exogenous IL-6 or IL-21 induces the expansion of Tfh cells, as previous findings mentioned above were based on the experiments using knockout mice and/or blockade antibodies. Moreover, the generation of Tfh cells is not completely impaired even in the absence of IL-6 and IL-21 (11). These results indicate that these

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

“…Because a previous report suggested that IL-7 facilitates the generation of Tfh cells (17), the induction of Tfh cells post-rRABV immunization was investigated. BALB/c mice (n ϭ 3) were intramuscularly (i.m.)…”

“…Because Tfh cells directly associate with GC B cells (17), the effect of IL-7 expressed by rRABV on GC B cells was evaluated. The inguinal LNs were collected at 7 and 14 dpi from BALB/c mice (n ϭ 3) that were individually immunized with 10 6 FFU of one of the rRABVs or with DMEM alone.…”

“…IL-7 is more efficient than IL-2 and IL-15 at increasing B cell differentiation from CD34 ϩ cord blood mononuclear cells in the presence of the same combination of stem cell factor and Flt3 ligand (16). The role of IL-7 in regulating the generation of Tfh cells and in the formation of GC B cells was defined in a recent study in which a mouse Fc-fused IL-7 was administered with a vaccine to combat challenge with a lethal influenza virus (17). To our knowledge, no previous studies have associated the expression of IL-7 with RABV immunization.…”

Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection

“…IL-7 is known to induce expansion of T cells under lymphopenic conditions (24). In our previous studies, we demonstrated that IL-7 can be used as a vaccine adjuvant to augment antigen-specific T cell response (25,26) and to enhance antibody responses through the induction of follicular helper T cells (27). Here, we demonstrate that a single intranasal pretreatment with Fc-fused IL-7 (IL-7-mFc), but not a native form of IL-7, completely protects mice from IAV-induced mortality for an extended period of time, even without preexisting IAV-specific immunity.…”

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

“…S1. Chinese hamster ovary (CHO) cells were stably transfected with a plasmid encoding IL7-Fc or G-CSF-Fc, and proteins were prepared as described previously (29). Recombinant human IL7 (rIL7), purified from HEK 293E cells, was purchased from BioLegend.…”