The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host-microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host-commensal microbial relationships and immune cell homeostasis in the intestine.

Intestinal epithelial cells: regulators of barrier function and immune homeostasis

In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota–host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy.

The microbiota in adaptive immune homeostasis and disease

Purpose of review Remarkable insights have been gleaned recently with regard to the pathophysiology of IgG4-related disease (IgG4-RD). These findings have direct implications for the development of targeted strategies for the treatment of this condition. Recent findings Oligoclonal expansions of cells of both the B and T lymphocyte lineages are present in the blood of patients with IgG4-RD. Oligoclonal expansions of plasmablasts are a good biomarker for disease activity. An oligoclonally expanded population of CD4+ cytotoxic T lymphocytes is found not only in the peripheral blood but also at tissue sites of active disease. This cell elaborates cytokines that may drive the fibrosis characteristic of IgG4-RD. T follicular helper cells (Tfhc), particularly the Tfhc2 subset, appear to play a major role in driving the class switch to IgG4 that typifies this disease. The relationship between malignancy and IgG4-RD remains an area of interest. Summary Advances in understanding the pathophysiology of IgG4-RD have proceeded swiftly, leading to the identification of a number of potential targeted treatment strategies. The completion of classification criteria for IgG4-RD, an effort supported jointly by the American College of Rheumatology and the European League Against Rheumatism, will further facilitate studies on this disease.

IgG4-related disease.

The cytokine TGF-β plays an integral role in regulating immune responses. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of effector and regulatory CD4(+) T cell responses. Many immune and nonimmune cells can produce TGF-β, but it is always produced as an inactive complex that must be activated to exert functional effects. Thus, activation of latent TGF-β provides a crucial layer of regulation that controls TGF-β function. In this review, we highlight some of the important functional roles for TGF-β in immunity, focusing on its context-specific roles in either dampening or promoting T cell responses. We also describe how activation of TGF-β controls its function in the immune system, with a focus on the key roles for members of the integrin family in this process.

/pdf/tgf-b-activation-and-function-in-immunity-4sm7dmz2jo.pdf

TGF-β Activation and Function in Immunity

The small intestine contains CD4 + CD8αα + double-positive intraepithelial lymphocytes (DP IELs), which originate from intestinal CD4 + T cells through down-regulation of the transcription factor Thpok and have regulatory functions. DP IELs are absent in germ-free mice, which suggests that their differentiation depends on microbial factors. We found that DP IEL numbers in mice varied in different vivaria, correlating with the presence of Lactobacillus reuteri . This species induced DP IELs in germ-free mice and conventionally-raised mice lacking these cells. L. reuteri did not shape the DP-IEL-TCR (TCR, T cell receptor) repertoire but generated indole derivatives of tryptophan that activated the aryl-hydrocarbon receptor in CD4 + T cells, allowing Thpok down-regulation and differentiation into DP IELs. Thus, L. reuteri , together with a tryptophan-rich diet, can reprogram intraepithelial CD4 + T cells into immunoregulatory T cells.

/pdf/lactobacillus-reuteri-induces-gut-intraepithelial-cd4-cd8aa-4dmf2o4gkn.pdf

Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells.

TCRαβ thymocytes differentiate into either CD8αβ(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4(+) T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II-restricted CD4(+) cytotoxic T lymphocytes.

/pdf/transcriptional-reprogramming-of-mature-cd4-helper-t-cells-2a73qmvhq6.pdf

Mohammad Mushtaq Husain

Papers

Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes

CD4 CTL: living up to the challenge.