Identification and characterization of CD8؉ T cells effectively controlling HIV-1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8 ؉ T cells have been only partially identified. In this study, we sought to identify CD8 ؉ T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identified 13 epitope-specific CD8 ؉ T cells controlling HIV-1 in Japanese individuals, though 9 of these epitopes were not previously reported. The breadths of the T cell responses to the 13 epitopes were inversely associated with plasma viral load (P ‫؍‬ 2.2 ؋ 10 ؊11 ) and positively associated with CD4 count (P ‫؍‬ 1.2 ؋ 10 ؊11 ), indicating strong synergistic effects of these T cells on HIV-1 control in vivo. Nine of these epitopes were conserved among HIV-1 subtype B-infected individuals, whereas three out of four nonconserved epitopes were cross-recognized by the specific T cells. These findings indicate that these 12 epitopes are strong candidates for antigens for an AIDS vaccine. The present study highlighted a strategy to identify CD8 ؉ T cells controlling HIV-1 and demonstrated effective control of HIV-1 by those specific for 12 conserved or cross-reactive epitopes. IMPORTANCEHLA-B*27-restricted and HLA-B*57-restricted cytotoxic T lymphocytes (CTLs) play a key role in controlling HIV-1 in Caucasians and Africans, whereas it is unclear which CTLs control HIV-1 in Asian countries, where HLA-B*57 and HLA-B*27 are very rare. A recent study showed that HLA-B*67:01 and HLA-B*52:01-C*12:02 haplotypes were protective alleles in Japanese individuals, but it is unknown whether CTLs restricted by these alleles control HIV-1. In this study, we identified 13 CTLs controlling HIV-1 in Japan by using comprehensive and exhaustive methods. They included 5 HLA-B*52:01-restricted and 3 HLA-B*67:01-restricted CTLs, suggesting that these CTLs play a predominant role in HIV-1 control. The 13 CTLs showed synergistic effects on HIV-1 control. Twelve out of these 13 epitopes were recognized as conserved or cross-recognized ones. These findings strongly suggest that these 12 epitopes are candidates for antigens for AIDS vaccines.

Differentiation of naïve CD4 T cells toward the T helper 1 (T H 1) and T helper 2 (T H 2) fates involves the transcriptional repression and enhancement, respectively, of Il4 and Il13, adjacent chromosome 11 genes encoding the canonical T H 2 cytokines interleukin-4 and interleukin-13. Proper execution of this developmental fate choice during immune responses is critical to host defense and, when misregulated, leads to susceptibility to infectious microbes and to allergic and autoimmune diseases. Here, using chromatin immunoprecipitation and real time reverse transcription PCR we identify the Polycomb family histone methyltransferase EZH2 as the enzyme responsible for methylating lysine 27 of histone H3 at the Il4-Il13 locus of T H 1 but not T H 2 cells, implicating EZH2 in the mechanism of Il4 and Il13 transcriptional silencing.

We analyzed the in vivo dynamics of peritoneal exudate cells (PECs) in mice injected with group A streptococcus (GAS). A live low-virulence strain, as well as heat-killed low- and high-virulence strains, significantly increased the number of PECs (primarily neutrophils), whereas a live high-virulence strain did not. When coinjected with thioglycollate, the live high-virulence strain, as well as most other GAS strains, suppressed the ability of thioglycollate to induce neutrophil exudation. This suppression was due to a cytocidal effect of GAS on exuded neutrophils rather than an inhibition of neutrophil migration. In addition, GAS enhanced the apoptosis of neutrophils. These cytocidal effects were significantly reduced by the deletion of functional streptolysin S from GAS. Our findings suggest that, in addition to the production of antiphagocytic factors and survival inside phagocytes, GAS uses a more aggressive method--the elimination of neutrophils--to evade the host's innate immune system.

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8 ؉ T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P ‫؍‬ 2 ؋ 10 ؊5 ). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ϳ90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8 ؉ T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8 ؉ T-cell response in all individuals, irrespective of HLA type.

T helper-2 (T H 2)-bias, the propensity of naive CD4 + T cells to differentiate into interleukin 4 (IL-4) secreting T H 2 cells, is a genetic trait impacting infectious, autoimmune and allergic disease susceptibility. T H 2-bias correlates with the amount of IL-4 initially secreted by newly activated T H cells that feeds back positively through the IL-4R-STAT6-GATA3 pathway to drive T H 2 development. Here, we identify Mina, a JmjC family member, as a genetic determinant of T H 2-bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, while its knockdown in primary CD4 + T cells led to Il4 derepression. Together, these findings provide mechanistic insight into an Il4 regulatory pathway controlling T H differentiation and genetic variation in T H 2-bias. Naive CD4 + T cells are multipotent sentinels of the immune system, poised to respond to instructive signals from antigen-presenting cells by differentiating into distinct effector cell lineages. These include T helper (T H ) 1 and T H 2 cells, differentially adapted for the control, respectively, of intra-and extracellular pathogens, in part via developmentally acquired potential for high expression of distinct cytokine genes 1 . Dysregulated CD4 + T cell development can promote susceptibility to infectious, autoimmune and allergic disease [2][3][4][5][6][7][8][9] .Interleukin 4 (IL-4) [http://www.signaling-gateway.org/molecule/query?afcsid=A001262], the canonical T H 2 effector cytokine, is also a critical developmental determinant, promoting Accession codesThe microarray data are deposited in RCAI RefDIC (URL: http://refdic.rcai.riken.jp/welcome.cgi) 50 under the following accession codes: RMSPTB007001 and RMSPTB008001. 11,12 to promote the differentiation of T H 2 cells possessing the capacity to secrete copious amounts of IL-4 10, 13-18 . Thus, regulation of autocrine IL-4 expression by activated T H cells is a key control point in T helper cell lineage commitment. Nonetheless, the molecular mechanism underlying this regulation is incompletely understood. Author contributions NIH Public AccessT H 2-bias is a complex genetic trait characterizing variation in the propensity of naive T H cells to differentiate into T H 2 (as opposed to T H 1) cells. T H 2-bias, measured experimentally as the amount of IL-4 produced by effector CD4 + T cells differentiated in vitro from naive T H cells activated under 'neutral' conditions (no exogenous cytokines added, except IL-2, and cultured without cytokine-specific antibodies), varies over 50-fold from the highproducer phenotype of BALB/c mice to the low-producer phenotype of B10.D2 mice and correlates with susceptibility to T H 2-dependent diseases such as bronchial asthma and leishmaniasis [14][15][16][19][20][21][22] . Various cellular mechanisms have been suggested as the basis for T H 2-bias, including variation in the sensitivity to prostaglandin 2 (PGE 2 )-dependent inhibition of interferon-γ (IFN-γ) production 23 , the timing of IL-1...