Different commensal bacterial species selectively initiate immune-mediated intestinal inflammation with distinctly different kinetics and anatomic distribution in the same host.

IntroductionTransplantation of cells and organs is regarded as the only therapeutic choice for end-stage failure of several organs and has been made possible by the development of powerful immunosuppressive treatments that prevent transplant rejection. However, most of these drugs nonspecifically target the immune response, leading to unwanted side effects, and have limited ability to prevent chronic rejection. 1,2 The ultimate goal in transplantation is, therefore, the induction of a sustained state of specific tolerance to donor alloantigens with minimization or complete withdrawal of immunosuppression. Many studies in rodents have shown that it is possible to exploit the mechanisms that normally maintain immune homeostasis and tolerance to self-antigens to induce tolerance to alloantigens. 3 Immunologic tolerance involves central and peripheral mechanisms. Central tolerance results from intrathymic deletion of T cells with high avidity for thymically expressed antigens. Peripheral tolerance can be achieved by various mechanisms including deletion of activated/effector T cells, anergy induction, and active regulation of effector T cells. 4,5 CD4 ϩ T cells with regulatory function have been shown to play a critical role in the maintenance of transplantation tolerance. 6 The CD25 ϩ fraction of CD4 ϩ T cells mediates tolerance on adoptive transfer into a naive host. 7-9 CD4 ϩ CD25 ϩ regulatory T (Treg) cells are a naturally occurring population of CD4 ϩ T cells that constitutively express the IL-2 receptor ␣-chain (CD25). 10 These cells were shown to be potent suppressors of activated T cells in vitro 11,12 and to be crucial for the control of autoreactive T cells 13 and of the effector function of alloreactive CD4 ϩ and CD8 ϩ T cells in transplantation models in vivo. 8,14 The precise mechanisms by which these Treg cells exert their suppressive function remain to be defined. Surface molecules such as cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), 15,16 the glucocorticoid-induced tumor necrosis factor receptor (GITR), 17 and cytokines such as TGF-␤ 18-20 and IL-10 8,21 are thought to play roles in different animal models.Several studies have implied that the regulation mediated by Treg cells is dependent on a continuous supply of alloantigens 8,[22][23][24] or tissue-specific target autoantigens, 25,26 suggesting that these cells have specificity for alloantigens or autoantigens. In transplantation, alloreactive CD4 ϩ T cells with indirect allospecificity are thought to play a key role in chronic rejection, and the control of these pathogenic effector cells by donor-specific Treg cells could, therefore, result in transplantation tolerance. [27][28][29][30][31] However, the possibility of using Treg cells as immunotherapy for the induction of antigen-specific tolerance is limited by cell number. Indeed, the entire pool of Treg cells accounts for only 5% to 10% of CD4 ϩ T cells in the peripheral blood of healthy persons. 10,32,33 In this study, we have explored whether in vivo alloresponses could be regulated...

T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC

Cancer classification aims to provide an accurate diagnosis of the disease and prediction of tumor behavior to facilitate oncologic decision making. Traditional breast cancer classification, mainly based on clinicopathologic features and assessment of routine biomarkers, may not capture the varied clinical courses of individual breast cancers. The underlying biology in cancer development and progression is complicated. Recent findings from high-throughput technologies added important information with regard to the underlying genetic alterations and the biological events in breast cancer. The information provides insights into new treatment strategies and patient stratifications that impact on the management of breast cancer patients. This review provides an overview of recent data on high throughput analysis of breast cancers, and it analyzes the relationship of these findings with traditional breast cancer classification and their clinical potentials.

CD4+ CD25 Additional supporting information may be found in the online version of this article at the publisher's web-site

Antigen presentation by activated human and rat CD4 ؉ T cells has long been known to induce hyporesponsiveness due to a combination of anergy and apoptosis. It has been assumed that no such phenomenon occurs in mice due to the inability of mouse T cells to synthesize major histocompatibility complex (

CD4+ CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+ CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the up-regulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (gammac) cytokines-IL-4, IL-7 and IL-15-had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the gammac cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+ CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.

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