The Role of CXCL13 in Antibody Responses to HIV-1 Infection and Vaccination

Abstract

CXCL13 signals through the G protein-coupled chemokine receptor CXCR5 to drive development of secondary lymphoid tissue as well as B cell and Tfh cell trafficking to germinal centers (GC), which leads to the differentiation of B cells to plasma cells and memory B cells. CXCL13 has been proposed as a general plasma biomarker for GC activities. In HIV-1 infected individuals, plasma CXCL13 levels have been associated with the rate of disease progression to AIDS. Moreover, CXCL13 production has been reported to be increased in HIV-1-infected lymph nodes, which may drive increased downregulation of CXCR5. In this review, we address the role of CXCL13 in HIV-1 infected individuals with regard to GC formation, generation of broadly neutralizing antibodies after infection and vaccination, and AIDS-related B cell lymphoma.

Keywords: CXCL13; CXCR5; HIV-1; broadly neutralizing antibodies; vaccine.

Figure 1

Tfh cells and CXCL13 in chronically HIV-1 infected individuals. Peptides (from vaccine/Ag)-loaded DCs migrate from the periphery to tissues/GC; cognate interaction of DCs with naïve/memory T cells and naïve/memory B cells induces the expression of BCL6, which in turn downregulates the expression of CCR7 and upregulates the expression of CXCR5 (1); cells migrate to the T cell-B cell border (2) for maturation and generation of short-lived plasma cells (3). B cells migrate to the dark zone of the GC (4); and undergo proliferation and somatic hypermutation (SHM) before migrating to the light zone (LZ) of the GC (5). Cellular interaction of GC B cells with Tfh cells (6) induces the production of long-lived plasma cells and memory B cells, and mediates somatic hypermutation, affinity maturation and class switch (7). However, excessive CXCL13 release from cells downregulates the expression CXCR5 in Tfh and B cells through autocrine/paracrine signaling (8), which impairs the successful interactions of these cells (6). Moreover, T follicular regulatory (Tfr) cells (9) regulate GC B cells, FDC and Tfh cell activities in the GC; it is evident that altered frequency of Tfr cells may account for the poor interaction of the GC B and Tfh cells observed in HIV-1 infection. These may increase the proportion of autoreactive Abs, exhausted B cells and poor response to vaccines/Ags, and collectively, may cause impairment of humoral responses (7). Ag, antigen; TCR, T cell receptor; BCR, B cell receptor; Tfh, T follicular helper cell; GC, germinal center; LZ, light zone; DZ, dark zone; SHM, somatic hypermutation; Tfr, T follicular regulatory; Ab, antibody.