SUMMARY The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4+ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1+CXCR5+ CD4+ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV+ individuals.

Experimental autoimmune encephalomyelitis (EAE) is an infl ammatory demyelinating disease of the central nervous system (CNS) induced in laboratory animals by active immunization with myelin antigens or by the adoptive transfer of myelin-specifi c CD4 + T cells. It is widely used as an animal model of multiple sclerosis (MS) and as a prototype of organ-specifi c autoimmunity. Until recently, EAE and MS were considered Th1 diseases, mediated by IL-12p70 -polarized, IFN-␥ -producing eff ector cells. This impression was based, in large part, on the association between clinical disease activity and expression of IFN-␥ and IL-12p40 (a subunit of IL-12p70) in CNS tissues, cerebrospinal fl uid, and circulating leukocytes ( 1 -3 ). In addition, activated macrophages are the predominant leukocyte in CNS infi ltrates of affl icted animals and patients, similar to the infi ltrates that characterize Th1-dependent hypersensitivity and antimicrobial responses in the periphery ( 4, 5 ).Recent fi ndings, however, suggest that the cytokine pathways underlying encephalitogenic T cell development and function are more complex than previously appreciated. Defi ciency of IL-17 or IL-23 (a heterodimeric monokine composed of IL-12p40 and p19 chains that expands and/or stabilizes Th17 cells) ( 6, 7 ) confers partial or complete resistance, respectively, against MOG 35-55 -induced EAE in C57BL/6 mice, whereas defi ciency of IFN-␥ or IL-12p70 does not ( 8 -10 ). Furthermore, myelin-specifi c

Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. Transcriptional regulators of human Tfh cell differentiation are poorly understood. In this article, we demonstrate that Bcl6 controls specific gene modules for human Tfh cell differentiation. The introduction of Bcl6 expression in primary human CD4 T cells resulted in the regulation of a core set of migration genes that enable trafficking to germinal centers: CXCR4, CXCR5, CCR7, and EBI2. Bcl6 expression also induced a module of protein expression critical for T–B interactions, including SAP, CD40L, PD-1, ICOS, and CXCL13. This constitutes direct evidence for Bcl6 control of most of these functions and includes three genes known to be loci of severe human genetic immunodeficiencies (CD40L, SH2D1A, and ICOS). Introduction of Bcl6 did not alter the expression of IL-21 or IL-4, the primary cytokines of human Tfh cells. We show in this article that introduction of Maf (c-Maf) does induce the capacity to express IL-21. Surprisingly, Maf also induced CXCR5 expression. Coexpression of Bcl6 and Maf revealed that Bcl6 and Maf cooperate in the induction of CXCR4, PD-1, and ICOS. Altogether, these findings reveal that Bcl6 and Maf collaborate to orchestrate a suite of genes that define core characteristics of human Tfh cell biology.

The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.