Evidence of innate lymphoid cell redundancy in humans.

Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.

The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women.

SHBG is the specific plasma transport protein for sex steroid hormones in humans. Plasma SHBG concentration follows a gender dimorphism but varies with nutritional and hormonal status in both sexes. In addition, a genetic influence on SHBG in humans has recently been suggested by family studies. We investigated the relationship between a point mutation (D327N) in SHBG gene exon 8 that delays human SHBG half-life and a pentanucleotide repeat polymorphism [PNRP (TAAAA)(n)] in the SHBG gene 5' untranslated region that influences transcription in vitro, on the one hand, and SHBG levels on the other, in a population of 303 women referred for hirsutism. Of these patients, 154 (51%) met the criteria for polycystic ovary syndrome (PCOS) and 124 (41%) were overweight [body mass index (BMI) > or = 25 kg/m(2)]. The two SHBG gene alleles for D327N substitution, wild-type (W) and variant (v), were identified by restriction fragment length polymorphism in the whole population, and the GeneScan method was used to identify PNRP alleles in 245 subjects. Six alleles of the pentanucleotide motif with six to 11 repeats were present in our population. Plasma SHBG concentration was related to PCOS status, non-SHBG-bound testosterone, BMI, fasting blood glucose level, fasting insulinemia, and D327N allele v. The v allele was associated with higher SHBG levels [36.9 +/- 15.9 nmol/liter for W/v (n = 52) and 43.5 +/- 3.5 nmol/liter for v/v (n = 2)] than was the wild-type W allele [31.1 +/- 16.1 nmol/liter (n = 249); P = 0.039]. Multivariate analysis showed that BMI, PCOS status, and D327N polymorphism influenced plasma SHBG concentrations, each of these parameters contributing independently of the others. Investigating the role of each allele of the TAAAA repeat polymorphism on SHBG levels was more complex because of the number of different genotypes (as many as 18 in our population) and the low frequency of some of them. Moreover, a strong disequilibrium linkage was found between D327N allele v and the eight-TAAAA repeat allele (P < 0.0001). This could mask the effect of the TAAAA repeat polymorphism on SHBG concentration in vivo. Nevertheless, SHBG levels in patients who were homozygous for six repeats (34.9 +/- 16.2 nmol/liter; n = 21) were significantly (P = 0.043) higher than in nine-repeat homozygous patients (21.5 +/- 13.0 nmol/liter; n = 8), and lay between the two for eight-repeat homozygous patients (28.5 +/- 15.8 nmol/liter; n = 44). Delineating the precise role of this PNRP polymorphism will need further investigation in a large healthy population. In summary, although BMI and PCOS status have a major influence on circulating SHBG levels in hirsute women, the present results support the notion that polymorphism(s) within the coding sequence and, potentially, in the regulatory sequence of the SHBG gene are associated with circulating SHBG levels and may represent part of the genetic background of sex steroid hormone activity in humans.