Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function

BACKGROUND: As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences. RESULTS: We examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition. CONCLUSIONS: Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-014-0106-0) contains supplementary material, which is available to authorized users

The Mst1 Kinase Is Required for Follicular B Cell Homing and B-1 B Cell Development

The Mst1 and 2 cytosolic serine/threonine protein kinases are the mammalian orthologs of the Drosophila Hippo protein. Mst1 has been shown previously to participate in T-cell and B-cell trafficking and the migration of lymphocytes into secondary lymphoid organs in a cell intrinsic manner. We show here that the absence of Mst1 alone only modestly impacts B cell homing to lymph nodes. The absence of both Mst1 and 2 in hematopoietic cells results in relatively normal B cell development in the bone marrow and does not impact migration of immature B cells to the spleen. However, follicular B cells lacking both Mst1 and Mst2 mature in the splenic white pulp but are unable to recirculate to lymph nodes or to the bone marrow. These cells also cannot traffic efficiently to the splenic red pulp. The inability of late transitional and follicular B cells lacking Mst 1 and 2 to migrate to the red pulp explains their failure to differentiate into marginal zone B cell precursors and marginal zone B cells. Mst1 and Mst2 are therefore required for follicular B cells to acquire the ability to recirculate and also to migrate to the splenic red pulp in order to generate marginal zone B cells. In addition B-1 a B cell development is defective in the absence of Mst1

A role for apoptosis-inducing factor in T cell development

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report that aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell-autonomous thymocyte developmental block associated with apoptosis at the β-selection stage, independent of T cell receptor β recombination. No abnormalities are observed in the B cell lineage. Transgenes encoding wild-type or DNA-binding–deficient mutant Aif rectify the thymic defect, but a transgene encoding oxidoreductase activity–deficient mutant Aif does not. The Hq thymic block is reversed in vivo by antioxidant treatment, and Hq T but not B lineage cells show enhanced oxidative stress. Thus, Aif, a ubiquitous protein, serves a lineage-specific nonredundant antiapoptotic role in the T cell lineage by regulating reactive oxygen species during thymic β-selection

Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα.

Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-κB α (IκBα) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling. Lymphotoxin β receptor (LTβR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-κB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IκBα mutant → Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IκBα deficiency and suggests that correction of this niche is critical for reconstituting their immune function

B cells and autoimmunity

There is a growing appreciation for the role for B cells in autoimmune disorders in which inflammation is driven by T cells, in addition to the well-established role for B cells in autoimmune disorders characterized by pathogenic auto-antibodies. Current information on tolerance checkpoints in B cells, B cell depletion, BAFF blockade, regulatory B cells and clonal ignorance mediated by the SIAE/Siglec pathway will be reviewed

Clonally expanded cytotoxic CD4+ T cells and the pathogenesis of IgG4-related disease

IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions, with dense lymphoplasmacytic infiltrates containing a preponderance of IgG4-expressing plasma cells. CD4+ T cells and B cells constitute the major inflammatory cell populations in IgG4-RD lesions. IgG4-RD patients with active, untreated disease show a marked expansion of plasmablasts in the circulation. Although the therapeutic depletion of B cells suggests a role for these cells in the disease, a direct role for B cells or IgG4 in the pathogenesis of IgG4-RD is yet to be demonstrated. Among the CD4+ T-cell subsets, Th2 cells were initially thought to contribute to IgG4-RD pathogenesis, but many previous studies were confounded by the concomitant history of allergic diseases in the patients studied and the failure to use multi-color staining to definitively identify T-cell subsets in tissue samples. More recently, using an unbiased approach to characterize CD4+ T-cell subsets in patients with IgG4-RD – based on their clonal expansion and ability to infiltrate affected tissue sites – CD4+ CTLs have been identified as the major CD4+ T-cell subset in disease lesions as well as in the circulation. CD4+ CTLs in affected tissues secrete pro-fibrotic cytokines including IL-1β, TGF-β1, and IFN-γ as well as cytolytic molecules such as perforin and granzymes A and B. In this review, we examine possible mechanisms by which activated B cells and plasmablasts may collaborate with the expanded CD4+ CTLs in driving the fibrotic pathology of the disease and describe the lacunae in the field and in our understanding of IgG4-RD pathogenesis

Laryngopharyngeal Reflux: Prospective Study Analyzing Various Nonsurgical Treatment Modalities for LPR

ABSTRACT Objective To compare the outcomes of various medical treatment modalities for laryngopharyngeal reflux (LPR). Study design Prospective study design. Materials and methods One-hundred and fifty patients were divided into three groups (A, B, C) based on the mode of intervention used for the control of LPR. Each study group enrolled 50 patients using random tables. • Group A: These patients were put on a twice daily dosage of esomeprazole (20 mg bd) and domeperidone (10 mg bd) for 4 months • Group B: These patients were put on bd dosage of esomeprazole (20 mg) and domeperidone (10 mg) and also received counseling for dietary and lifestyle changes. The duration of treatment was for 4 months. • Group C: These patients received, in addition to above, 10 mg of amitriptyline (tricyclic antidepressant) bid, again for 4 months. Results The success achieved in controlling LPR was defined as greater than 50% improvement in baseline symptoms. The success achieved in group A was 46%, in group B was 54% and in group C was 40%. The relative change in reflux symptom index (RSI) over any given period of time was significantly higher than the relative change in reflux finding score (RFS). The relative change in RSI over first month was 30.99%, which is significantly higher than the relative change of RFS (6.39%) over the same period. The mean RSI scores during 4 months of treatment fell from 20.67 to 8.9 (p &lt; 0.01) in group A, from 23.3 to 8.6 (p &lt; 0.01) and from 21.3 to 10.8 (p &lt; 0.05) in group C. The mean RFS during 4 months fell from 15 to 6.5 (p &lt; 0.05) in group A, from 16 to 6.4 (p &lt; 0.05) and from 15 to 6.4 (p &lt; 0.05) in group C. Conclusion • All the three interventions had a statistically significant impact on the signs and symptoms of LPR. • However, higher success rates were achieved in group B where patients were put on a bid dosage esomeprazole and domeperidone nad counseled for lifestyle and dietary changes. Paradoxically, success rates achieved in group C was lower than other groups, possibly because of the anticholinergic effects of amitriptyline causing dry mouth and dry throat. • The symptomatic improvement was seen much earlier than the improvement in laryngoscopic findings. This was evidenced by the fact that relative change in RSI was much higher than the relative change of RFS over a given period of time. • If diagnosed with enough surety and certainty, patients of LPR do not need any antidepressant medications as these medications may not have any role in the treatment of same and may, however, worsen the condition owing to their anticholinergic side effects. How to cite this article Mattoo O, Muzaffar R, Mir A, Yousuf A Charag AH, Ahmad R. Laryngopharyngeal Reflux: Prospective Study Analyzing Various Nonsurgical Treatment Modalities for LPR. Int J Phonosurg Laryngol 2012;2(1):5-8. </jats:sec