Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4+ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.

https://science.sciencemag.org/content/sci/280/5362/427.full.pdf

Gastrointestinal Tract as a Major Site of CD4+ T Cell Depletion and Viral Replication in SIV Infection

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.

/pdf/primary-hiv-1-infection-is-associated-with-preferential-1hbq76jkd9.pdf

Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract.

Mouse gut intraepithelial lymphocytes (IEL) consist mainly (90%) of two populations of CD8+ T cells. One bears heterodimeric alpha/beta CD8 chains (Lyt-2+, Lyt-3+), a T cell receptor (TCR) made of alpha/beta chains, and is Thy-1+; it represents the progeny of T blasts elicited in Peyer's patches by antigenic stimulation. The other bears homodimeric alpha/alpha CD8+ chains, contains no beta chain mRNA, and is mostly Thy-1- and TCR-gamma/delta + or -alpha/beta +; it is thymo-independent and does not require antigenic stimulation, as shown by its presence: (a) in nude and scid mice; (b) in irradiated and thymectomized mice repopulated by T-depleted bone marrow cells bearing an identifiable marker; (c) in thymectomized mice treated by injections of monoclonal anti-CD8 antibody, which lead to total depletion of peripheral CD8+ T lymphocytes; and (d) in germ-free mice and in suckling mice. In young nude mice, alpha/alpha CD8 chains, CD3-TCR complexes, and TCR mRNAs (first gamma/delta) are found on IEL, while they are not detectable on or in peripheral or circulating lymphocytes or bone marrow cells. IEL, in contrast to mature T cells, contain mRNA for the RAG protein, which is required for the rearrangement of TCR and Ig genes. We propose that the gut epithelium (an endoderm derivative, as the thymic epithelium) has an inductive property, attracting progenitors of bone marrow origin, and triggering their TCR rearrangement and alpha/alpha CD8 chains expression, thus giving rise to a T cell population that appears to belong to the same lineage as gamma/delta thymocytes and to recognize an antigenic repertoire different from that of alpha/beta CD8+ IEL.

/pdf/two-gut-intraepithelial-cd8-lymphocyte-populations-with-119gll3upo.pdf

Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation.

The lymphoid tissues associated with the intestine are exposed continuously to antigen and are the largest part of the immune system. Many lymphocytes are found in organised tissues such as the Peyer's patches and mesenteric lymph nodes, as well as scattered throughout the lamina propria and epithelium of the mucosa itself. These lymphocyte populations have several unusual characteristics and the intestinal immune system is functionally and anatomically distinct from other, peripheral compartments of the immune system. This review explores the anatomical and molecular basis of these differences, with particular emphasis on the factors which determine how the intestinal lymphoid tissues discriminate between harmful pathogens and antigens which are beneficial, such as food proteins or commensal bacteria. These latter antigens normally provoke immunological tolerance, and inappropriate responses to them are responsible for immunopathologies such as food hypersensitivity and inflammatory bowel disease. We describe how interactions between local immune cells, epithelial tissues and antigen-presenting cells may be critical for the induction of tolerance and the expression of active mucosal immunity. In addition, the possibility that the intestine may act as an extrathymic site for T-cell differentiation is discussed. Finally, we propose that, under physiological conditions, immune responses to food antigens and commensal bacteria are prevented by common regulatory mechanisms, in which transforming growth factor beta plays a critical role.

The anatomical basis of intestinal immunity.

ummary
Background
Probiotics are defined as live micro-organisms which confer a health benefit on the host. Although most probiotics are bacteria, one strain of yeast, Saccharomyces boulardii, has been found to be an effective probiotic in double-blind clinical studies.

Aims
To compare the main properties that differentiates yeast from bacteria and to review the properties of S. boulardii explaining its potential benefits as a probiotic.

Methods
The PubMed and Medline databases were searched using the keywords ‘probiotics’, ‘yeast’, ‘antibiotic associated diarrhea’, ‘Saccharomyces boulardii’,‘bacterial diarrhea’ and ‘inflammatory bowel disease’ in various combinations.

Results
Several clinical studies have been conducted with S. boulardii in the treatment and prevention of various forms of diarrhoea. Promising research perspectives have been opened in terms of maintenance treatment of inflammatory bowel diseases. The mechanism of S. boulardii’s action has been partially elucidated.

Conclusion
Saccharomyces boulardii is a strain of yeast which has been extensively studied for its probiotic effects. The clinical activity of S. boulardii is especially relevant to antibiotic-associated diarrhoea and recurrent Clostridium difficile intestinal infections. Experimental studies clearly demonstrate that S. boulardii has specific probiotic properties, and recent data has opened the door for new therapeutic uses of this yeast as an ‘immunobiotic’.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2007.03442.x

Review article: yeast as probiotics-saccharomyces boulardii

Recently, T cell subpopulations presumably representing memory T lymphocytes have been described in vitro. Intestinal lamina propria T cells (LP-T) have characteristics resembling those of memory cells. We therefore investigated the expression of surface Ag associated with memory phenotype in vitro on lamina propria lymphocytes (LPL) and PBL and on the T cell subpopulations defined by the bright expression of CD45R0 by flow cytometric analysis of isolated cell populations. LPL had significantly increased percentages of CD45R0 and CD58 positive cells compared with PBL. Whereas PBL showed bimodal expression profiles of CD45R0, CD58, and CD2, the vast majority of LPL was bright for these Ag. Expression of CD45RA was significantly reduced in both frequency and intensity in LPL, and LPL had significantly reduced percentages of CD11a/CD18 and CD29 positive cells compared with PBL. The CD45R0 bright T cell subpopulations of both PBL and LPL were characterized by a lack of CD45RA. CD45R0 bright T cells from the peripheral blood (PB-T) were predominantly bright for CD2, CD58, CD29, and CD11a/CD18 whereas CD45R0 dim PB-T had bimodal expression profiles and CD45R0 negative PB-T were dim or even negative for these Ag. CD45R0 bright LP-T were also bright for CD2 and CD58 but had significantly reduced surface densities of CD11a/CD18 and CD29 compared with CD45R0 bright PB-T. The surface density of CD29 on CD45R0 bright LP-T corresponded to that of CD45R0 negative PB-T, and a significant proportion of CD45R0 bright LP-T was even negative for CD11a/CD18 and CD29. Additionally, CD45R0 bright LP-T in contrast to PB-T were characterized by a lack of 1-selectin and the expression of CDw49a and the mucosa-specific T cell Ag HML-1 on high percentages of cells. Our results show that the phenotype of CD45R0 bright T cells from the lamina propria clearly deviates from that of memory T cells in vitro and of CD45R0 bright T cells in the peripheral blood. We conclude that memory T cell populations in vivo undergo specific differentiation depending on their tissue localization, leading to unique phenotypic and presumably functional features.

T cell differentiation antigens on lymphocytes in the human intestinal lamina propria

The Ag recognized by the mAb HML-1 is expressed on more than 90% of human intestinal intraepithelial lymphocytes, whereas in other lymphoid tissues it is rarely or not expressed. In the present study, we have investigated the percentage of HML-1-positive cells in the human intestinal lamina propria and the coexpression of HML-1 with different T cell subset markers. In addition, we studied the inducibility of HML-1 on PBL which normally are HML-1-negative. Flow cytometric analysis of isolated intestinal lamina propria lymphocytes (LPL) showed that about 40% of the cells expressed HML-1, the majority belonging to the CD8-positive subpopulation. Virtually all LPL expressed CD45RO, whereas the percentage of CD29-positive cells was only about 50%, similar to PBL. There were only few cells expressing CD45RA or Leu-8 in the lamina propria. HML-1-positive cells were almost exclusively CD45RA-negative, but were found in both the CD29-positive and the CD29-negative subpopulation of LPL. In vitro stimulation of PBL showed that the expression of HML-1 was inducible on T cells by mitogens, phorbolester, Ag, and rIL-2. Expression of HML-1 was induced with a different time course and with differences in the response to the investigated stimuli compared with CD25. Activated HML-1-positive PBL were also predominantly CD45RA-negative. The findings show that HML-1 is an Ag, which is expressed in vivo on a specific subset of previously activated T cells in the unique environment of the intestinal mucosa, and which can be induced in vitro by different activation signals on PBL.

The HML-1 antigen of intestinal lymphocytes is an activation antigen.

Saccharomyces boulardii (Sb) is used for the prevention and treatment of diarrhea of different etiologies We prospectively investigated the effects of Sb on lymphocytes and duodenal mucosa Before and after oral administration of Sb for 3 weeks, circulating and intestinal lymphocytes were isolated and characterized by flow cytometry Trophic effects on duodenal mucosa were investigated by morphometry and determination of brush border enzyme activity Results were compared intraindividually before and after Sb In intestinal lymphocytes no phenotypic changes were observed CD4+ cells of the peripheral blood had a significantly increased expression of CD25 (p < 002) None of twelve volunteers had an increase in villous surface area (ns) Immunoglobulin A content in small intestine secretion was unaltered An increase in brush border enzyme activity of lactase, α-glucosidase, and alkaline phosphatase was observed (p < 001) Our findings indicate that Sb has a positive effect on the maturation of enterocytes and only a minor influence on lymphocytes

Immunological and trophical effects of Saccharomyces boulardii on the small intestine in healthy human volunteers.

γδ T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium

Lamina propria T cells have a low expression of the CD45RA antigen and a high expression of the CD45RO antigen. This phenotype is characteristic for memory T cells (table 2). In addition, T cells in the effector compartment of the mucosa bear surface antigens which are very rarely found in other sites of the immune system. Intestinal T cells also express functional IL-2 receptors and IL-2 receptor α chain mRNA, and are able to synthesize high amounts of IL-2. However, another marker of memory T cells, CD29, is not expressed in high density in the lamina propria indicating that lamina propria T cells differ from ‘classical’ memory T cells. This is supported by functional studies in nonhuman primates infected rectally withC. trachomatis which show that lamina propria T cells do not proliferate after stimulation with antigen but rather provide helper function for immunoglobulin synthesis (table 2). The intestinal lamina propria therefore contains highly specialized T cells which have a distinctive phenotype and are activated. Functionally these T cells can be characterized as differentiated effector lymphocytes which respond to triggering the antigen-specific T cell receptor by secreting helper factors for B cells. This concept is supported by recent studies showing that the pattern of lymphokines produced by lamina propria T cells and the responsiveness to certain lymphokines differ from those of other lymphocyte populations [25]. Lamina propria T cells thus represent a subset of memory T cells with a unique maturational state.

H L Schieferdecker

Papers

T cell differentiation antigens on lymphocytes in the human intestinal lamina propria

The HML-1 antigen of intestinal lymphocytes is an activation antigen.

Immunological and trophical effects of Saccharomyces boulardii on the small intestine in healthy human volunteers.

γδ T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium

Phenotype and function of lamina propria T lymphocytes