CD8+ Regulatory T Cell - A Mystery to Be Revealed.

Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3+CD4+ Tregs are well established, much of CD8+ Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8+ T cells have been named "CD8+ Treg" and mainly focus on CD122hiLy49+CD8+ Tregs present in naïve mice. CD122hiLy49+CD8+ Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-ß (Transforming growth factor-ß) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8+ Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8+ Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4+ TFR (follicular regulatory T cells) and CD8+ Tregs.

Regulatory effects of dexamethasone on NK and T cell immunity.

Glucocorticoids (GCs) act via the intracellular glucocorticoid receptor (GR), which can regulate the expression of target genes. With regard to the immune system, GCs may affect both innate and adaptive immunity. Our study analyzed the immunoregulatory effects of dexamethasone (Dex) treatment on splenic T, Treg, NK and NKT cells by treating C57Bl6 mice with various doses of Dex. We observed that treatment with Dex decreased the number of NK cells in the spleen and suppressed their activity. In particular, the expression of both Ly49G and NKG2D receptors was decreased by Dex. However, Dex did not affect the population of NKT cells. With regard to splenic T cells, our results show a dose-dependent reduction in CD3+, CD4+, CD8+, CD44+ and CD8+CD122+ T cells, but a stimulatory effect on CD4+CD25+ regulatory T cells by Dex treatment. In addition, treatment with Dex suppressed anti-tumor immune response in a mouse EG7 tumor model. We conclude that Dex may suppress both T- and NK-mediated immunity.

The Broad Spectrum of Human Natural Killer Cell Diversity.

Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56bright and CD56dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

Uterine natural killer cell partnerships in early mouse decidua basalis.

The decidua basalis of developing mouse implantation sites is highly enriched in CD45+ leukocytes. In intact, syngeneically mated C57BL/6 decidua basalis examined at gestation day 8.5 by whole-mount in situ immunohistochemistry, leukocyte, but not trophoblast, conjugations were reported. Nothing is known regarding time course, frequency, composition, or importance of physiologic decidual CD45+ cell pairing. In this study, we confirmed the presence of anti-CD54+/anti-CD11a+ immune synapses in CD45+ decidual cell conjugates and characterized their cellular heterogeneity. Conjugated cell pairs were virtually absent before implantation (virgin and gestation days 3.5 and 4.5), were infrequent at gestation day 5.5, but involved 19% of all CD45+ cells by gestation day 8.5, then declined. By gestation day 8.5, almost all CD45+ cells coexpressed CD31, and 2 CD45+CD31+ cells composed most conjugates. Conjugation partners were defined for 2 nonoverlapping uterine natural killer cell subsets (Ly49C/I +/Dolichos biflorus agglutinin lectin- and Ly49C/I-/Dolichos biflorus agglutinin lectin+). Ly49C/I+ uterine natural killer cells were the major subset from before mating up to gestation day 6.5. At gestation day 5.5/6.5, uterine natural killer cell conjugates involving Ly49C/I + cells were more abundant. By gestation day 8.5/9.5, Dolichos biflorus agglutinin lectin+ uterine natural killer cells were the dominant subset with Dolichos biflorus agglutinin lectin+/Dolichos biflorus agglutinin lectin+ homologous conjugates and Dolichos biflorus agglutinin lectin+/Dolichos biflorus agglutinin lectin- heterologous conjugates dominating uterine natural killer cell pairings. At gestation day 6.5, both Ly49C/I+/CD45+ and Dolichos biflorus agglutinin lectin+/CD45+ heterologous conjugate pairs strongly engaged antigen-presenting cells (CD11c+, CD68+, or major histocompatibility complex class II+). By gestation day 8.5, dominant partners of Ly49C/I+/CD45+ and Dolichos biflorus agglutinin lectin+/CD45+ heterologous conjugates are T cells (CD8+ >CD4+). Heterologous conjugates that did not involve uterine natural killer cells occurred but did not suggest antigen presentation to T cells. These data identify gestation day 6.5-8.5 in the pregnant mouse as a critical window for leukocyte interactions that may establish immune regulation within implantation sites.

Two complementary rat NK cell subsets, Ly49s3+ and NKR-P1B+, differ in phenotypic characteristics and responsiveness to cytokines.

Two major subsets of rat NK cells can be distinguished based on their expression of the Ly49s3 or the NKR-P1B lectin-like receptor. Ly49s3(+) NK cells, but not NKR-P1B(+) NK cells, express a wide range of Ly49 receptors. Here, we have examined differences between these two subsets in their expression of certain NK cell-associated molecules as well as their responses to cytokines. A microarray analysis suggested several differentially expressed genes, including preferential expression of NKG2A/C receptors by NKR-P1B(+) NK cells. This was confirmed by staining with tetramers of RT.BM1, the putative ligand of CD94/NKG2, indicating that Ly49 and CD94/NKG2 receptors separate into distinct NK cell compartments. Further, expression of CD25 by Ly49s3(+) NK cells was associated with more rapid proliferation in response to IL-2 as compared with NKR-P1B(+) NK cells. Thus, certain inflammatory situations may preferentially expand the Ly49s3(+) NK cells. Moreover, freshly isolated Ly49s3(+) and NKR-P1B(+) NK cells produce similar amounts of cytokines, and a minor Ly49s3(-)NKR-P1B(-) double-negative NK subset appears to be hyporesponsive based on its significantly lower IFN-gamma production. Collectively, our data demonstrate divergent profiles of NKR-P1B(+) and Ly49s3(+) NK cells, indicating distinct tasks in vivo.

Murine CXCR3+CD27bright NK cells resemble the human CD56bright NK-cell population.

Human NK cells can be subdivided into CD56(dim) and CD56(bright) NK cells, which exhibit different phenotypical and functional characteristics. As murine NK cells lack CD56 or a distinct correlate, direct comparative studies of NK cells in mice and humans are limited. Although CD27 is currently proposed as a feasible subset marker in mice, we assume that the usage of this marker alone is insufficient. We rather investigated the expression of the chemokine receptor CXCR3 for its suitability for distinguishing murine NK-cell subsets with simultaneous consideration of CD27. Compared with CXCR3(-) NK cells, exerting stronger cytotoxic capability, CXCR3+ NK cells displayed an activated phenotype with a lower expression of Ly49 receptors, corresponding to human CD56(bright) NK cells. Also in common with human CD56(bright) NK cells, murine CXCR3+ NK cells exhibit prolific expansion as well as robust IFN-gamma, TNF-alpha and MIP-1alpha production. We additionally demonstrated changes in both CXCR3 and CD27 expression upon NK-cell activation. In summary, CXCR3 serves as an additional applicable marker for improved discrimination of functionally distinct murine NK-cell subsets that comply with those in humans.