Han-Qing Jiang

Cutting Edge: Recent Immune Status Determines the Source of Antigens That Drive Homeostatic T Cell Expansion

Homeostatic proliferation of naive T cells transferred to T cell-deficient syngeneic mice is driven by low-affinity self-MHC/peptide ligands and the cytokine IL-7. In addition to homeostatic proliferation, a subset of naive T cells undergoes massive proliferation in chronically immunodeficient hosts, but not in irradiated normal hosts. Such rapid T cell proliferation occurs largely independent of homeostatic factors, because it was apparent in the absence of IL-7 and in T cell-sufficient hosts devoid of functional T cell immunity. Strikingly, immunodeficient mice raised under germfree conditions supported only slow homeostatic proliferation, but not the marked T cell proliferation observed in conventionally raised immunodeficient mice. Thus, polyclonal naive T cell expansion in T cell-deficient hosts can be driven predominantly by either self-Ags or foreign Ags depending on the host’s previous state of T cell immunocompetency.

Restricted IgA repertoire in both B-1 and B-2 cell-derived gut plasmablasts

Mucosal IgA is the most abundantly produced Ig upon colonization of the intestinal tract with commensal organisms in the majority of mammals. The repertoire of these IgA molecules is still largely unknown; a large amount of the mucosal IgA cannot be shown to react with the inducing microorganisms. Analysis of the repertoire of used H chain Ig (VH) genes by H-CDR3 spectrotyping, cloning, and sequencing of VH genes from murine intestinal IgA-producing plasma cells reveals a very restricted usage of VH genes and multiple clonally related sequences. The restricted usage of VH genes is a very consistent observation, and is observed for IgA plasma cells derived from B-1 or conventional B-2 cells from different mouse strains. Clonal patterns from all analyzed VH gene sequences show mainly independently acquired somatic mutations in contrast to the clonal evolution patterns often observed as a consequence of affinity maturation in germinal center reactions in peripheral lymphoid organs and Peyer’s patches. Our data suggest a model of clonal expansion in which many mucosal IgA-producing B cells develop in the absence of affinity maturation. The affinity of most produced IgA might not be the most critical factor for its possible function to control the commensal organisms, but simply the abundance of large amounts of IgA that can bind with relatively unselected affinity to redundant epitopes on such organisms.

T cell control of the gut IgA response against commensal bacteria

In humans and most experimental mammals the gut lamina propria (LP) is the site of prodigious synthesis of the IgA isotype of immunoglobulin (Ig) and its secretion into the lumen. The major part of total Ig synthesis occurs here, leading to questions concerning the possible specific and non-specific stimuli of its production and the usefulness of this product to the host. Clearly, this typically continuous output of IgA is not constitutive as axenic (germ free (GF)) and newborn humans and other mammals display few secretory IgA plasmablasts in gut LP and minimal levels of secreted IgA in their gut lumen.1 2 In some way, colonisation with members of the normal gut microbiota seem to initiate the development and chronic activity of certain elements of the humoral mucosal immune system.3 4 This IgA consists of specific antibodies identifiably reactive with colonising bacteria, as well as of large quantities of IgA that cannot be shown to have been stimulated by or be reactive with particular antigens (Ags) present in food or microbes—so called “natural” IgA. In the mouse, the apparent duality of the IgA response might be explained by a difference in origin: firstly, conventional B cells (also called B2 cells) are specifically stimulated by microbial Ags and benefit from cognate interaction with Ag specific CD4+ T cells. They are clonally expanded in germinal centre reactions (GCR) in Peyers patches (PP) and mesenteric lymph nodes, and benefit from the positive selection process occurring in GCR leading to affinity maturation that results in specific IgA antibodies.5 6 Secondly, a separate lineage of B cells, termed B1 cells, can be observed in the mouse. These cells, originally defined by expression of the surface marker CD5 and high expression of IgM, arise early in ontogeny, reside in the peritoneal and pleural …

Distinct Mechanisms for Cross-Protection of the Upper Versus Lower Respiratory Tract Through Intestinal Priming

A main feature of the common mucosal immune system is that lymphocytes primed in one mucosal inductive site may home to distant mucosal effector sites. However, the mechanisms responsible for such cross-protection remain elusive. To address these we have used a model of local mucosal infection of mice with reovirus. In immunocompetent mice local duodenal priming protected against subsequent respiratory challenge. In the upper respiratory tract this protection appeared to be mainly mediated by specific IgA- and IgG2a-producing B cells, whereas ex vivo active effector memory CTL were found in the lower respiratory tract. In accordance with these findings, clearance of reovirus from the lower respiratory tract, but not from the upper respiratory tract, of infected SCID mice upon transfer of gut-primed lymphocytes depended on the presence of T cells. Taken together this study reveals that intestinal priming leads to protection of both the upper and lower respiratory tracts, however through distinct mechanisms. We suggest that cross-protection in the common mucosal immune system is mediated by trafficking of B cells and effector memory CTL.

Early bacterial dependent induction of inducible nitric oxide synthase (iNOS) in epithelial cells upon transfer of CD45RBhigh CD4+ T cells in a model for experimental colitis

Background: Both the role of inducible nitric oxide synthase (iNOS) in the development of inflammatory bowel disease (IBD) as well as the molecular details governing its mucosal induction remain unclear. Methods: In the present study we evaluated the role of the residing intestinal microflora in the induction of epithelial iNOS upon transfer of CD45RBhigh CD4+ T cells to SCID mice. CB‐17 SCID mice were reared with conventional flora (CNV) or germfree CB‐17 SCID mice were monoassociated with Helicobacter muridarum, act A(−) mutant Listeria monocytogenes, segmented filamentous bacteria (SFB), or Ochrobactrum anthropi. Results: Within 2 weeks CNV SCID mice injected with CD45RBhigh CD4+ T cells showed a focal, epithelial iNOS expression on the apical site of villi that preceded the infiltration of CD4+ T cells and cytokine production followed by extension of this expression to the entire surface along the whole crypt axis as the colitis progressed. SCID mice monoassociated with H. muridarum developed a severe colitis and showed high epithelial iNOS expression. CNV‐SCID mice without T cells and SCID mice monoassociated with SFB did not show any iNOS expression, whereas SCID mice monoassociated with act A(−) mutant L. monocytogenes and O. anthropi showed some scattered epithelial iNOS staining on the apical site of a few villi, but none of these mice developed colitis. Conclusions: These findings demonstrate that the expression of epithelial iNOS is highly bacterium‐specific and correlates with the severity of disease, suggesting an important role for this enzyme in the development of IBD. (Inflamm Bowel Dis 2007)

Chapter 18 – The Role of Mucosal Microbiota in the Development, Maintenance, and Pathologies of the Mucosal Immune System

This chapter discusses the role of mucosal microbiota in the development, maintenance, and pathologies of the mucosal immune system. Most mucosal sites of lymphoid tissue—respiratory tract, adenoids, salivary glands, and urogenital tract—in healthy mammals are in a quiescent state and generally resemble the status of lymphoid areas in spleen and most peripheral lymph nodes (PLN). The intestinal tract, palatine tonsils, and occasionally the nasal-associated lymphoid tissue (NALT) are the exceptions. These mucosal lymphoid tissues are in a “physiologically normal state of inflammation.” The chapter focuses on how the intestinal microbes drive the development of gut-associated lymphoid tissue (GALT) during neonatal life and act to maintain its physiologically normal steady state of inflammation. Specific and adaptive, “natural” and semi-specific, and aspecific elements of the mucosal immune systems may benefit and be activated by host interactions with environmental antigens (Ags). To provide the experimental rationale for implicating intestinal or oral/nasal microflora in the development of GALT, palatine tonsil, and sometimes NALT and their steady state of inflammation, the chapter briefly contrasts the status of systemic lymphoid tissue in healthy mammals—spleen, PLN—with GALT, palatine tonsils, and NALT.