Oral Probiotic Control Skin Inflammation by Acting on Both Effector and Regulatory T Cells

Probiotics are believed to alleviate allergic and inflammatory skin disorders, but their impact on pathogenic effector T cells remains poorly documented. Here we show that oral treatment with the probiotic bacteria L. casei (DN-114 001) alone alleviates antigen-specific skin inflammation mediated by either protein-specific CD4+ T cells or hapten-specific CD8+ T cells. In the model of CD8+ T cell-mediated skin inflammation, which reproduces allergic contact dermatitis in human, inhibition of skin inflammation by L. casei is not due to impaired priming of hapten-specific IFNγ-producing cytolytic CD8+ effector T cells. Alternatively, L. casei treatment reduces the recruitment of CD8+ effector T cells into the skin during the elicitation (i.e. symptomatic) phase of CHS. Inhibition of skin inflammation by L. casei requires MHC class II-restricted CD4+ T cells but not CD1d-restricted NK-T cells. L casei treatment enhanced the frequency of FoxP3+ Treg in the skin and increased the production of IL-10 by CD4+CD25+ regulatory T cells in skin draining lymph nodes of hapten-sensitized mice. These data demonstrate that orally administered L. casei (DN-114 001) efficiently alleviate T cell-mediated skin inflammation without causing immune suppression, via mechanisms that include control of CD8+ effector T cells and involve regulatory CD4+ T cells. L. casei (DN-114 001) may thus represent a probiotic of potential interest for immunomodulation of T cell-mediated allergic skin diseases in human

Cross-talk between cd1d-restricted nkt cells and γδ cells in t regulatory cell response

CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR) recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection

Abnormal Changes in NKT Cells, the IGF-1 Axis, and Liver Pathology in an Animal Model of ALS

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4+ T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress

NKT cells play critical roles in the induction of oral tolerance by inducing regulatory T cells producing IL-10 and transforming growth factor β, and by clonally deleting antigen-specific T cells

Oral tolerance is the systemic unresponsiveness induced by orally administered proteins. To explore the roles of natural killer T (NKT) cells in oral tolerance, we induced oral tolerance to ovalbumin (OVA) in NKT cell-deficient mice. In CD1d(–/–) mice, the induction of tolerance to orally administered high- or low-dose OVA was impaired. Dendritic cells (DCs) in the Peyer's patches (PPs) of CD1d(–/–) mice fed OVA showed high expression of major histocompatibility complex (MHC) class II and B7 molecules, whereas DCs of control mice fed OVA expressed low levels of these molecules. The adoptive transfer of NKT cells restored oral tolerance and induction of tolerogenic DCs in the PPs and spleens of CD1d(–/–) mice. Moreover, interleukin (IL)-10 and transforming growth factor (TGF)-β1 production in vitro were reduced in cells from the spleen and PPs of CD1d(–/–) mice compared with those of control mice fed OVA. The numbers of OVA-specific CD4(+) KJ1-26(+) T cells were significantly reduced in the PPs and spleens of DO11·10 mice fed OVA. In contrast, OVA-specific CD4(+) KJ1-26(+) T cells were not deleted in the PPs or spleens of DO11·10 CD1d(–/–) mice. In conclusion, NKT cells were found to play an indispensable role in oral tolerance by inducing regulatory T cells, and clonally deleting antigen-specific CD4(+) T cells

Subcongenic analysis of genetic basis for impaired development of invariant NKT cells in NOD mice.

Reduced numbers and function of invariant NKT (iNKT) cells partially contribute to type 1 diabetes (T1D) development in NOD mice. Previous linkage analysis identified a genetic locus on chromosome 2 controlling numbers of thymic iNKT cells. Interestingly, this locus resides within the Idd13 region that distinguishes NOD mice from the closely genetically related, but strongly T1D-resistant NOR strain. Thus, we tested if a genetic variant that confers T1D resistance in NOR mice may do so by enhancing iNKT cell numbers. iNKT cells were enumerated by an alpha-GalCer analog loaded CD1d tetramer in NOD and NOR mice as well as in NOD stocks carrying NOR-derived congenic regions on chromosome 1, 2, or 4. Significantly, more thymic and splenic iNKT cells were present in NOR than NOD mice. The NOR-derived Idd13 region on chromosome 2 contributed the most significant effect on increasing iNKT cell numbers. Subcongenic analyses indicated that at least two genes within the Idd13 region regulate iNKT cell numbers. These results further define the genetic basis for numerical iNKT cell defects contributing to T1D development in NOD mice