ABSTRACTEnteric fever caused bySalmonella entericaserovar Paratyphi A infection has emerged as an important public health problem. Recognizing that in randomized controlled field trials oral immunization with attenuatedS. entericaserovar Typhi live vaccine Ty21a conferred significant cross-protection againstS. Paratyphi B but notS. Paratyphi A disease, we undertook a clinical study to ascertain whether humoral immune responses could explain the field trial results. Ty21a immunization of adult residents of Maryland elicited predominantly IgA antibody-secreting cells (ASC) that recognizeS. Typhi lipopolysaccharide (LPS). Cross-reactivity toS. Paratyphi A LPS was significantly lower than that toS. Paratyphi B LPS. ASC producing IgG and IgA that bind LPS from each of theseSalmonellaserovars expressed CD27 and integrin α4β7 (gut homing), with a significant proportion coexpressing CD62L (secondary lymphoid tissue homing). No significant differences were observed in serum antibody against LPS of the different serovars. Levels of IgA B memory (BM) cells toS. Typhi LPS were significantly higher than those againstS. Paratyphi A or B LPS, with no differences observed betweenS. Paratyphi A and B. The response of IgA BMto outer membrane proteins (OMP) fromS. Typhi was significantly stronger than that to OMP ofS. Paratyphi A but similar to that to OMP ofS. Paratyphi B. The percentages of IgG or IgA BMresponders to LPS or OMP from theseSalmonellastrains were similar. Whereas cross-reactive humoral immune responses toS. Paratyphi A or B antigens are demonstrable following Ty21a immunization, they cannot explain the efficacy data gleaned from controlled field trials.

Significance Efforts to develop an efficacious HIV vaccine have been unsuccessful to date. Efficacy trials have reported that recombinant Ad5 (rAd5)-HIV vaccines were not efficacious and unexpectedly associated with excess HIV infection in vaccine recipients. Understanding the underlying mechanisms is urgent and will further HIV vaccine design. By comparing human CD4 T cells specific to Ad5 and CMV, we report that natural exposure- or vaccine-induced Ad5-specific CD4 T cells are highly susceptible to HIV compared with CMV-specific CD4 T cells and selectively manifest a Th17-like proinflammatory phenotype. Our findings suggest a potential mechanism for rAd5-associated excess HIV infections in vaccine recipients and highlight that testing HIV susceptibility of vaccine-generated CD4 T cells may have utility before vaccine evaluation in human trials.

S almonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, is the causative agent of typhoid fever, the most prevalent form of enteric fever, resulting in an estimated 21.7 million cases and 200,000 deaths per year worldwide (1). However, infection with Salmonella enterica serovar Paratyphi A (paratyphoid A fever) or Salmonella enterica serovar Paratyphi B (paratyphoid B fever) causes similar clinical manifestations (2). While less prevalent than typhoid fever, paratyphoid fever occurs in an estimated 5.4 million cases each year (3-6). Recent reports indicate that paratyphoid A fever is on the rise in areas of endemicity (e.g., South and Southeast Asia, China) and among travelers returning from those areas (3-6). The emergence of multiple antibiotic-resistant Salmonella strains has increased the health risks posed by these enteric fever infections (7).Currently, two licensed vaccines against typhoid fever are available worldwide, parenteral Vi polysaccharide (Vi) and oral live attenuated Ty21a. Nevertheless, each of these vaccines exhibits limitations that have fostered the development of a new generation of vaccines, including both of the engineered live oral typhoid vaccines (e.g., CVD 908-htrA [⌬aroC ⌬aroD ⌬htrA] and CVD 909 [CVD 908-htrA further engineered to constitutively express Vi]) (8) and the M01ZH09 (⌬aroC ⌬ssaV) (9) and Vi carrier protein conjugate vaccines (10). There are, however, no available licensed vaccines against S. Paratyphi A or B.Whole-genome comparative analysis has revealed a high degree of homology among S. Typhi, S. Paratyphi A, and S. Paratyphi B at the DNA level, suggesting the theoretical potential for vaccines against S. Typhi to offer some degree of cross-protection against S. Paratyphi A and S. Paratyphi B (11,12). Vi-based vaccines cannot confer cross-protection, since neither S. Paratyphi A nor S. Paratyphi B expresses Vi antigen. In contrast, large-scale field trials of the efficacy of the oral Ty21a vaccine have documented a moderate level of cross-protection against S. Paratyphi B but not against S. Paratyphi A (13-15). Therefore, the development of an effective vaccine against S. Paratyphi A has emerged as a public health priority (16).We and others have extensively studied the induction of S. Typhi-specific humoral and cellular immune responses (cell-mediated immunity [CMI]) following immunization with Ty21a and other live oral typhoid vaccines in humans (9,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) and have also begun to explore the cross-reactive immune responses elicited by the S. Typhi live oral vaccines against S. Paratyphi A and S. Paratyphi B that might explain the observed cross-protection and its serovar limitations (29,30).The capacity of oral typhoid vaccines to induce humoral responses has been well documented, but information on the functional capacity of the induced antibodies has been sparse except for a few reports on specific antibody-enhanced phagocytosis and intracellular killing. In the 1980s, Tagliabue et al. reported that the Ig...

The Ikaros zinc finger (IkZF) transcription factor Eos is a known regulator of CD4+ regulatory T cell (TREG) populations. However, its role in the differentiation of other CD4+ T cell subsets is unknown. Here, we find that Eos deficiency results in both compromised TH1 cell differentiation and reduced production of the TH1 effector cytokine IFN-γ. Historically, IkZF factors have been associated with changes in gene expression via the alteration of chromatin structure. However, ATAC-seq analysis indicated that there were minimal changes in chromatin accessibility between wild type and Eos-deficient cells cultured under TH1-polarizing conditions. Rather, we find that IL-2 signaling promotes the STAT5-dependent induction of Eos expression, and that Eos both interacts with STAT5 and supports tyrosine phosphorylation-mediated STAT5 activation. Consequently, STAT5 enrichment is reduced at TH1 target genes in the absence of Eos. Thus, modulation of STAT5 signaling represents a novel mechanism by which Eos positively regulates the TH1 gene program. Given the important role for IL-2/STAT5 signaling in the differentiation of TH2, TH9, and TREG cell subsets, it will be of interest to determine whether this mechanism is conserved across additional CD4+ T cell populations.