Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted.

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGFß sources. Alterations in the cellular networks induced by loss of TGFßRII expression revealed a model consistent with TGFß promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

Obesity Modulates Intestinal Intraepithelial T Cell Persistence, CD103 and CCR9 Expression, and Outcome in Dextran Sulfate Sodium-Induced Colitis.

Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αß and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αß and γδ IEL persistence as obesity progresses with a different mechanism in αß versus γδ IEL populations. CD4+ and CD4+CD8+ αß intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αß and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium-induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.

Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection.

Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population.

Id2 regulates hyporesponsive invariant natural killer T cells.

While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, α-galactosylceramide (αGalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells.

Innate immunity in donor procurement.

PURPOSE OF REVIEW: Ischaemic kidney injury occurs during organ procurement and can lead to delayed graft function or nonviable grafts. The innate immune system is a key trigger of inflammation in renal ischaemia. This review discusses the components of innate immunity known to be involved in renal ischaemic reperfusion injury (IRI). Understanding how inflammatory damage is initiated in renal IRI is important for the development of targeted therapies aimed at preserving the donor organ. RECENT FINDINGS: Much remains to be determined about the role of innate immune signalling in renal ischaemia/reperfusion injury. Recently, discoveries about complement receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs) and inflammasomes have opened new avenues of exploration. We are also now learning that macrophages, complement and TLR activation may have additional roles in renal repair following IRI. SUMMARY: A greater understanding of the mechanisms that contribute to innate immune-mediated renal ischaemic damage will allow for the development of therapeutics targeted to the donor organ. New data suggest that treatment limited to specific receptors on specific cells, or localized to specific regions within the kidney, may provide novel approaches to maximize our use of donor organs, particularly those that may have been discarded due to prolonged preimplantation ischaemia.

Immunomodulation at epithelial sites by obesity and metabolic disease.

Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options.

Memory-like CD8+ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells.

Naive T cells proliferate in response to lymphopenia and acquire the phenotypic and functional qualities of memory T cells, providing enhanced protection against infection. How well memory-like T cells generated during lymphopenia-induced homeostatic proliferation (HP)-memory differentiate into secondary memory cells and compete with Ag-experienced true-memory cells is unknown. We found that CD8(+) HP-memory T cells generated robust responses upon infection and produced a secondary memory population comparable to true-memory cells in the absence of competition. However, when true-memory and HP-memory T cells competed during infection, HP-memory cells contributed less to the effector population, contracted earlier, and formed fewer secondary memory cells. Furthermore, HP- and true-memory cells demonstrated distinct chemokine receptor expression and localization within the spleen during infection, indicating differential access to signals necessary for secondary memory formation. Thus, HP-memory T cells provide protection without compromising the true-memory population. Differences in HP- and true-memory T cells may reveal the basis of competition for limited resources within the memory-T cell compartment.

Transcriptional regulator Id2 mediates CD8+ T cell immunity.

Transcriptional programs that initiate and sustain the proliferation, differentiation and survival of CD8(+) T cells during immune responses are not completely understood. Here we show that inhibitor of DNA binding 2 (Id2), an antagonist of E protein transcription factors, was upregulated in CD8(+) T cells during infection and that expression of Id2 was maintained in memory CD8(+) T cells. Although Id2-deficient naive CD8(+) T cells recognized antigen and proliferated normally early after infection, effector CD8(+) T cells did not accumulate because the cells were highly susceptible to apoptosis. Id2-deficient CD8(+) T cells responding to infection had changes in the expression of genes that influence survival and had altered memory formation. Our data emphasize the importance of Id2 in regulating gene expression by CD8(+) T cells and the magnitude of effector responses, suggesting a mechanism involving Id protein- and E protein-mediated survival and differentiation of mature T cells.