A. Xu

Phenotypic and functional characteristic of a newly identified CD8+Foxp3−CD103+ regulatory T cells

TGF-β and Foxp3 expressions are crucial for the induction and functional activity of CD4(+)Foxp3(+) regulatory T (iTreg) cells. Here, we demonstrate that although TGF-β-primed CD8(+) cells display much lower Foxp3 expression, their suppressive capacity is equivalent to that of CD4(+) iTreg cells, and both Foxp3(-) and Foxp3(+) CD8+ subsets have suppressive activities in vitro and in vivo. CD8(+)Foxp3(-) iTreg cells produce little IFN-γ but almost no IL-2, and display a typical anergic phenotype. Among phenotypic markers expressed in CD8(+)Foxp3(-) cells, we identify CD103 expression particularly crucial for the generation and function of this subset. Moreover, IL-10 and TGF-β signals rather than cytotoxicity mediate the suppressive effect of this novel Treg population. Therefore, TGF-β can induce both CD8(+)Foxp3(-) and CD8(+)Foxp3(+) iTreg subsets, which may represent the unique immunoregulatory means to treat autoimmune and inflammatory diseases.

Allelic distribution of HLA class I genes in the Tibetan ethnic population of China

Tibetans live in Qinghai‐Tibet Plateau rising about 4000 m a.s.l. in south‐west China. Archaeological evidences suggested that there have been humans living in Tibet at least 5000 years ago. However, Tibetan earlier history remains elusive. In the present study, allelic distribution of human leucocyte antigen (HLA)‐A, ‐B and ‐Cw in 158 unrelated Tibetan Chinese was investigated using sequencing‐based typing methods, and a total of 25 HLA‐A, 45 HLA‐B and 20 HLA‐Cw alleles were identified. A*24G1 (27.2%), B*51G1 (16.8%), Cw*04G1 (13.3%) and Cw*070201G1 (13.3%) are the most common HLA‐A, ‐B and ‐Cw alleles. The most frequently detected haplotypes were A*24G1‐B*51G1‐Cw*140201 (3.6%), A*24G1‐B*51G1 (6.8%), A*02G1‐Cw*070201G1 (6.5%) and B*51G1‐Cw*140201 (5.0%). Chi‐squared test suggested that all three loci fitted the Hardy–Weinberg expectations. No evidence for a departure from selective neutrality at the HLA‐A and ‐B loci was observed. However, significant departure of the observed homozygosity from the expected values was found for HLA‐Cw. Though the contemporary Tibetans inhabit the south‐west China, Neis genetic distance measure based on frequencies of HLA‐A, ‐B and ‐Cw indicated that Tibetans were closer to northern Han Chinese, Mongolian Chinese, Koreans and Japanese rather than to southern Han Chinese. The corresponding dendrogram constructed according to the neighbour‐joining method supported that Tibetans separated from southern Han and located in North‐East Asian cluster which included northern Han Chinese and Mongolian Chinese. These data were in good agreement with language classification and with a recent hypothesis that Tibetan might originate from northern China along Yellow river.

TGF-β–Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism

Foxp3+ regulatory T cells (Treg) playing a crucial role in the maintenance of immune tolerance and prevention of autoimmune diseases consist of thymus-derived naturally occurring CD4+Foxp3+ Treg cells (nTreg) and those that can be induced ex vivo with TGF-β (iTreg). Although both Treg subsets share similar phenotypes and functional characteristics, they also have potential biologic differences on their biology. The role of iTreg in regulating B cells remains unclear so far. The suppression assays of Treg subsets on activation, proliferation, and Abs production of B cells were measured using a Treg and B cell coculture system in vitro. Transwell and Ab blockade experiments were performed to assess the roles of cell contact and soluble cytokines. Treg were adoptively transferred to lupus mice to assess in vivo effects on B cells. Like nTreg, iTreg subset also directly suppressed activation and proliferation of B cells. nTreg subset suppressed B cell responses through cytotoxic manner related to expression of granzyme A, granzyme B, and perforin, whereas the role of iTreg subset on B cells did not involve in cytotoxic action but depending on TGF-β signaling. Furthermore, iTreg subset can significantly suppress Ab produced by lupus B cells in vitro. Comparison experiments using autoantibodies microarrays demonstrated that adoptive transfer of iTreg had a superior effect than nTreg subset on suppressing lupus B cell responses in vivo. Our data implicate a role and advantage of iTreg subset in treating B cell–mediated autoimmune diseases, boosting the translational potential of these findings.

Polymorphism of HLA class I genes in Meizhou Han population of Guangdong, China

Human leukocyte antigen (HLA) is an invaluable marker for anthropological studies because of its extreme polymorphism. Most of the studies carried out in Chinese populations are about HLA class II genes, but few about class I genes. In the present study, we investigated HLA class I polymorphism using polymerase chain reaction‐sequencing‐based typing (PCR‐SBT) method in 104 unrelated Han individuals in Meizhou of Guangdong, southern China. Twenty‐three HLA‐A, 43 HLA‐B and 27 HLA‐C alleles were identified and allele frequencies and two‐locus (C/B) and three‐locus (A/C/B) haplotypes were statistically analysed. The most frequent HLA‐A allele is A*110101 with a frequency of 30.3%, followed by A*24020101 (22.2%) and A*2420 (11.6%). Among the 43 detected HLA‐B alleles, B*5801 (17.0%), B*400101 (15.5%) and B*4601 (10.0%) were frequently observed. Among the 27 detected C alleles, the most predominant one is Cw*07020101 (25.8%), followed by Cw*0717 (14.7%). The most frequent HLA‐C/B two‐locus haplotype is Cw*07020101/B*400101 (10.1%). The most common HLA‐A/C/B three‐locus haplotype in Meizhou Han is A*110101/Cw*07020101/B*400101 (3.4%). Phylogenetic tree based on HLA class I allele frequencies genetically suggested that Meizhou Han has an affinity to southern Asian populations. The result may also reflect an admixture of Han and ethnic minorities of southern China.

Characterization and sequence analysis of the novel HLA‐Cw*040105 allele in a Chinese Uygur individual

A novel human leukocyte antigen (HLA) allele, HLA-Cw*040105, was identified in a Chinese Uygur individual. It differs from the closest allele Cw*04010101 by four nucleotides at position nt 60 (C>T) in exon 1, genomic nt 477 (A>T) in intron 2, nt 835(T>C), and nt 850 (C>T) in exon 3.

A novel HLA-DRB1*15 allelic sequence isolated from the Han population of Guangdong, China.

A novel DRB1*15 allele, DRB1*1516, has been identified in a Guangdong Han individual. Its sequence was confirmed by sequencing of polymerase chain reaction products and clones. This allele differed by one nucleotide from DRB1*150101 at position 220 (G→A), resulting in an amino acid substitution from Gly to Arg at codon 45.

Characterization of a novel DRB1*14 allele (DRB1*1449) in the Han‐Chinese population

We report here a novel human leukocyte antigen (HLA) allele, DRB1*1449, in the Han‐Chinese population. The nature of the new allele was confirmed by the sequencing‐based typing (SBT) method. Genomic DNA and six subclones containing DNA fragment of DRB1 exon 2 were sequenced in both forward and reverse directions. The exon 2 nucleotide sequence of DRB1*1449 is closely related to DRB1*1432 allele based on sequence homology. It has four nucleotide (nt) substitutions at positions 71, 196, 244 and 245 in exon 2, which lead to changes of amino acid sequences. The serological assignment of DRB1*1449 is DR14 based on the serological HLA typing result. This novel allele might be a result of recombination between DRB1*1402 and DRB1*140101 like alleles, which are very common among Chinese population.