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How the immune system maintains peripheral tolerance under inflammatory conditions is poorly understood. Here we assessed the fate of gastritogenic T cells following inflammatory activation in vivo. Self-reactive T cells (A23 T cells) specific for the gastric H+ /K+ ATPase α subunit (HKα) were transferred into immunosufficient recipient mice and immunised at a site distant to the stomach with adjuvant containing the cognate HKα peptide antigen. Activation of A23 T cells by immunisation did not impact on either immune tolerance or protection from gastric autoimmunity in wild-type BALB/c mice. However, increased presentation of endogenously derived HKα epitopes by dendritic cells (DCs) in the gastric lymph node of IE-H+ /K+ β transgenic mice (IEβ) reduces A23 T-cell tolerance to gastric antigens after inflammatory activation, with subsequent development of gastritis. While HKα-specific A23 T cells from immunised wild-type mice were poorly responsive to in vitro antigen specific activation, A23 T cells from immunised IEβ transgenic mice were readily re-activated, indicating loss of T-cell anergy. These findings show that DCs of gastric lymph nodes can maintain tolerance of pathogenic T cells following inflammatory stimulation and that the density of endogenous antigen presented to self-reactive T cells is critical in the balance between tolerance and autoimmunity.

Selection of T cells does not end with events in the thymus, but continues in extrathymic tissues and for the life of the organism. In this review, we examine how self-reactive T cells are rendered harmless and the processes that select for T cells that are most efficient at combating pathogens. The implications of peripheral T-cell selection for the immune response as animals age are discussed as is the critical role of dendritic cells in directing T-cell differentiation.

Although the transcription factor Foxp3 is implicated in regulating glucocorticoid-induced TNF receptor (GITR) expression in the T regulatory cell lineage, little is known about how GITR is transcriptionally regulated in conventional T cells. In this study, we provide evidence that TCR-mediated GITR expression depends on the ligand affinity and the maturity of conventional T cells. A genetic dissection of GITR transcriptional control revealed that of the three transcription factors downstream of the classical NF-κB pathway (RelA, cRel, and NF-κB1), RelA is a critical positive regulator of GITR expression, although cRel and NF-κB1 also play a positive regulatory role. Consistent with this finding, inhibiting NF-κB using Bay11-7082 reduces GITR up-regulation. In contrast, NFAT acts as a negative regulator of GITR expression. This was evidenced by our findings that agents suppressing NFAT activity (e.g., cyclosporin A and FK506) enhanced TCR-mediated GITR expression, whereas agents enhancing NFAT activity (e.g., lithium chloride) suppressed TCR-mediated GITR up-regulation. Critically, the induction of GITR was found to confer protection to conventional T cells from TCR-mediated apoptosis. We propose therefore that two major transcriptional factors activated downstream of the TCR, namely, NF-κB and NFAT, act reciprocally to balance TCR-mediated GITR expression in conventional T cells, an outcome that appears to influence cell survival.

The mucosal addressin cellular adhesion molecule 1 (MAdCAM) is expressed on the venules of the gut associated lymphoid tissue (GALT); it is also expressed on the venules of the lobules of the mammary gland. We have previously found that MAdCAM-targeting using a rat anti-MAdCAM monoclonal Ab as both antigen and targeting moiety resulted in an enhanced local IgA gut response. We therefore surmised that such targeting may also enhance IgA responses in the mammary gland. We show that our model antigen localizes to the lobules of the mammary glands as well as the GALT, but not to the draining lymph nodes and that targeting MAdCAM results in secretory IgA responses in the milk. We provide evidence that this milk IgA Ab is of a secretory nature and is consistent with derivation from gut plasmablasts that have migrated to the mammary gland. Targeting MAdCAM may be a way for a novel vaccine strategy that affords protection to the mammary gland and the suckling neonate.

International audience; Two Bordetella bronchiseptica mutants, lacking the adenylate cyclase (Cya) or both Cya and pertactin (Prn), were compared with their parental strain NL1013 in their abilities to colonize the nose of neonate piglets and to induce local and systemic antibody responses against filamentous hemagglutinin (FHA) after intranasal (i.n.) inoculation. The number of bacteria recovered and the duration of infection in the nasal secretions were greater for the wild-type parent strain than for the Cya-deficient mutant, indicating that Cya plays an important role during B. bronchiseptica colonization of the nasal cavity. The double mutant did not colonize the nasal cavity and was less able to adhere to epithelial cells in vitro than the other two strains, supporting the hypothesis that Prn plays a major role in cell adhesion. In piglets inoculated with the wild type strain, anti-FHA IgM was found in the nasal secretions one week after inoculation, followed two weeks later by anti-FHA IgA; their presence was concomitant with decreases in bacterial counts. Anti-FHA IgG appeared at six weeks after infection in the serum. In contrast, i.n. inoculation with either mutant failed to induce a nasal secretory antibody response but did induce an earlier and higher IgM response in the serum than inoculation with the wild type strain. However, only the Cya-deficient mutant was able to prime the piglets for the development of a secondary nasal IgM and serum IgG response to FHA after intranasal inoculation with the wild type B. bronchiseptica.

The pharyngeal (Ph) and palatine (Pa) tonsils, although located in different regions of the upper aero-digestive tract (UADT), are thought to protect the respiratory tract similarly against infections by inducing and disseminating T and surface IgA(+) (sIgA(+)) B cells. We investigated the factors controlling the migratory properties of T and sIgA(+) B lymphocytes in the UADT of pigs by comparing the expression of vascular addressins, homing receptors and chemokine transcripts in Ph/Pa tonsils, Peyer's patches (PP) and their draining lymph nodes (LN). The vascular addressin PNAd was detected on high endothelial venules in both tonsils, whereas mucosal addressin cell adhesion molecule-1, otherwise present in PP and mesenteric LN, was not detected. More importantly, the vascular cell adhesion molecule-1 (VCAM-1) addressin was present in Ph tonsil and LN but neither in Pa tonsil nor in PP vascular cells, whereas both T and sIgA(+) B lymphocytes displayed similar levels of alpha4beta1(high) integrin, the ligand of VCAM-1. Analysis of transcript levels for several lymphoid (CCL19, CXCL12 and CCL21) and epithelial chemokines also demonstrated opposite chemokine mRNA ratios for Ph tonsil (CCL28 > CCL25) and PP, with Pa tonsil expressing very low levels of CCL28. Collectively, these data indicate that the differential compartmentalization of sIgA(+) lymphocytes between Pa and Ph tonsils may partly result from the differential expression of VCAM-1 and CCL28. They also suggest that tonsillar addressins and epithelial chemokines, rather than the cells intravasating it, control the regionalization of sIgA(+) lymphocytes in the UADT.