Deena Gibbons

Mouse and human intestinal immunity: same ballpark, different players; different rules, same score

The study of animal immune physiology and animal models of human disease have accelerated many aspects of translational research by allowing direct, definitive investigations. In particular, the use of mice has allowed genetic manipulation, adoptive transfer, immunization, and focused cell and tissue sampling, which would obviously be unthinkable for studies in humans. However, the disease relevance of some animal models may be uncertain and difficulties in interpretation may occur as a consequence of immunological differences between the two species. In this review, we will consider general differences in the structure and development of human and mouse mucosal lymphoid microenvironments and then discuss species differences in mucosal B- and T-cell biology that relate to the current concepts of intestinal immune function.

Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γδ T Cell Compartments

Summary Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments.

The gut mucosal immune system in the neonatal period

Invasive sepsis in the newborn period is a major cause of childhood morbidity and mortality worldwide. The infant immune system undoubtedly differs intrinsically from the mature adult immune system. Current understanding is that the newborn infant immune system displays a range of competencies and is developing rather than deficient. The infant gut mucosal immune system is complex and displays a plethora of phenotypic and functional irregularities that may be clinically important. Various factors affect and modulate the infant gut mucosal immune system: components of the intestinal barrier, the infant gut microbiome, nutrition and the maternal–infant hybrid immune system. Elucidation of the phenotypic distribution of immune cells, their functional significance and the mucosa‐specific pathways used by these cells is essential to the future of research in the field of infant immunology.

Brokering the peace: the origin of intestinal T cells

In designating the thymic origin of the cells, the T in T cell seems simple enough, and the impressive unfolding of how the differentiation and selection of conventional CD4 and CD8 T cells are supported by the uniquely capable thymic stroma seems prima facie to leave little left to uncover. But, as the initial uncovering of T-cell receptor (TCR) γ-chain genes forewarned, there are myriad “unconventional T cell” subtypes whose development is not easily explained by current understanding. Such cells, either TCRαβ+ or TCRγδ+, rarely express either CD4 (a coreceptor for major histocompatibility complex (MHC) II) or CD8αβ (a coreceptor for MHC I).2 Instead, they are CD4, CD8 double-negative (DN) or express a homomeric CD8αα molecule. However, rather than being mere fringe players, worthy only of “page 2, column 3,”3 these unconventional T cells compose a substantial fraction of perhaps the most abundant and most active T cells in the body—the intraepithelial lymphocytes (IELs)—that populate several body surfaces, including the gut. There, they seemingly contribute to the physiologic homeostasis that embraces epithelial integrity, the measured immune response to commensals, and the adaptive tolerance toward self-antigens. When this homeostasis is disrupted, IELs may also contribute to inflammatory and wound-healing responses. Given this, a strong interest in their origin is appropriate.

Cutting Edge: Regulator of G Protein Signaling-1 Selectively Regulates Gut T Cell Trafficking and Colitic Potential

The RGS1 gene is associated with celiac disease, multiple sclerosis, and type I diabetes, which are all T cell-mediated pathologies, yet there is no reported analysis of regulator of G protein signaling (RGS)1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS1 depletion selectively enhances such chemotaxis in gut T cells and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease.

Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization.

BACKGROUND Infection or stimulation of the innate immune system by nonspecific microbial antigens is thought to educate the immune system to respond appropriately to allergens, preventing allergy. OBJECTIVE To determine the immunologic pathways that might explain how infection/microbial exposure inhibits allergic sensitization. METHODS Immunologic studies of non-antigen-specific functions of CD8 memory cells, their maturation in vivo, and their effects in a mouse asthma model, to test the hypothesis that CD8 memory is shaped by innate immunity in a way that can inhibit allergic disease. RESULTS We found that CD8 memory T-cell (CD8 Tm) populations bridge innate and adaptive immunity by responding to either antigen or cytokines alone. CD8 Tm populations partially subvert the clonal selection process by activating their neighbors through induction of dendritic cell IL-12. Stimulation of innate or acquired immunity in the lung or gut causes expansion/maturation of CD8 Tm populations, which provide an early source of cytokines, enhance T(H)1 immunity, and inhibit allergic sensitization and airway inflammation/hyperresponsiveness in a non-antigen-specific fashion. CONCLUSION CD8 T-cell-mediated immune memory is long-lived and can retain its capacity for rapid cytokine release in a nonantigen-specific fashion. This novel type of memory enhances T(H)1 over T(H)2 immunity and prevents allergic sensitization after exposure to environmental antigens or infection.

αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.

Abstract Background and Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7–E-cadherin interactions. Methods: αEβ7+ and αEβ7− colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. Results: CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7− T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7− lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. Conclusion: αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology.

Suppression of airway inflammation by a natural acute infection of the intestinal epithelium

Although chronic intestinal helminth infections may suppress allergen-induced airway pathology by inducing a combination of modified T-helper (Th) 2 and immunosuppressive cytokines, a similar capacity of natural acute intestinal infections has remained untested, despite their global prevalence. Here, we show that allergic airway phenotypes including eosinophilia, eotaxin mRNA, and Th2 cytokines are significantly suppressed in animals that were infected by and that have cleared the intestinal parasite Eimeria vermiformis. Unlike in helminth-infected animals, regulation requires temporal coincidence of infection with sensitization; depends on interferon-γ; and is not associated with an enhanced antigen-specific immunoglobulin G1 response. Moreover, regulation was effective following allergen sensitization in different anatomical sites, and in young and adult mice. These data highlight a transient anatomical dissemination of “functional immunologic dominance” following infection of the gut mucosa. They strongly support the hypothesis that airway allergies are naturally suppressed by both acute and chronic mucosal pathogens, but by different mechanisms.

Short-term and long-term effects of caesarean section on the health of women and children

A caesarean section (CS) can be a life-saving intervention when medically indicated, but this procedure can also lead to short-term and long-term health effects for women and children. Given the increasing use of CS, particularly without medical indication, an increased understanding of its health effects on women and children has become crucial, which we discuss in this Series paper. The prevalence of maternal mortality and maternal morbidity is higher after CS than after vaginal birth. CS is associated with an increased risk of uterine rupture, abnormal placentation, ectopic pregnancy, stillbirth, and preterm birth, and these risks increase in a dose-response manner. There is emerging evidence that babies born by CS have different hormonal, physical, bacterial, and medical exposures, and that these exposures can subtly alter neonatal physiology. Short-term risks of CS include altered immune development, an increased likelihood of allergy, atopy, and asthma, and reduced intestinal gut microbiome diversity. The persistence of these risks into later life is less well investigated, although an association between CS use and greater incidence of late childhood obesity and asthma are frequently reported. There are few studies that focus on the effects of CS on cognitive and educational outcomes. Understanding potential mechanisms that link CS with childhood outcomes, such as the role of the developing neonatal microbiome, has potential to inform novel strategies and research for optimising CS use and promote optimal physiological processes and development.

Regulated T-cell development: a victim of multiple conspiracies

Over about 400 million years there has been a conserved subdivision of T cells into those bearing a γδ T-cell receptor (TCR) and those bearing an αβ TCR. No one is sure why this is, but the two cell types have some interesting distinguishing characteristics, particularly their antigen specificities and their anatomical homing.1 In addition, the development of γδ cells seems always to precede that of αβ T cells. This is a good thing for γδ cells, because the TCRδ locus lies embedded within the TCRα locus, and when TCR Vα and Jα gene segments rearrange, they delete the TCRδ genes. Unchecked, this would substantially reduce the chances of making γδ cells.