Role of antigen specific T and B cells in systemic and mucosal immune responses in ETEC and Shigella infections, and their potential to serve as correlates of protection in vaccine development

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses

Journal of Experimental Medicine ◽

10.1084/jem.190.7.895 ◽

1999 ◽

Vol 190 (7) ◽

pp. 895-902 ◽

Cited By ~ 280

Author(s):

Anthony J. Coyle ◽

Clare Lloyd ◽

Jane Tian ◽

Trang Nguyen ◽

Christina Erikkson ◽

...

Keyword(s):

Immune Responses ◽

T Helper Cell ◽

Helper Cell ◽

Eosinophil Infiltration ◽

Cell Type ◽

T Helper ◽

Helper Cell Type ◽

Mucosal Immune Responses

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

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The Role of Dendritic Cells, B Cells, and M Cells in Gut-Oriented Immune Responses

The Journal of Immunology ◽

10.4049/jimmunol.166.8.4843 ◽

2001 ◽

Vol 166 (8) ◽

pp. 4843-4852 ◽

Cited By ~ 121

Author(s):

Oral Alpan ◽

Gregory Rudomen ◽

Polly Matzinger

Keyword(s):

Dendritic Cells ◽

B Cells ◽

Immune Responses ◽

M Cells

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Parenteral Vaccination Can Be an Effective Means of Inducing Protective Mucosal Responses

Clinical and Vaccine Immunology ◽

10.1128/cvi.00214-16 ◽

2016 ◽

Vol 23 (6) ◽

pp. 438-441 ◽

Cited By ~ 20

Author(s):

John D. Clements ◽

Lucy C. Freytag

Keyword(s):

Experimental Data ◽

Immune Responses ◽

Vaccine Development ◽

Effective Means ◽

Rare Occurrence ◽

Mucosal Tissues ◽

Mucosal Immune Responses ◽

Paradigm Shifting ◽

Current Paradigm ◽

The Way

ABSTRACTThe current paradigm in vaccine development is that nonreplicating vaccines delivered parenterally fail to induce immune responses in mucosal tissues. However, both clinical and experimental data have challenged this concept, and numerous studies have shown that induction of mucosal immune responses after parenteral vaccination is not a rare occurrence and might, in fact, significantly contribute to the protection against mucosal infections afforded by parenteral vaccines. While the mechanisms underlying this phenomenon are not well understood, the realization that parenteral vaccination can be an effective means of inducing protective mucosal responses is paradigm-shifting and has potential to transform the way vaccines are designed and delivered.

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B-1a B Cells that Link the Innate and Adaptive Immune Responses Are Lacking in the Absence of the Spleen

Journal of Experimental Medicine ◽

10.1084/jem.20011140 ◽

2002 ◽

Vol 195 (6) ◽

pp. 771-780 ◽

Cited By ~ 185

Author(s):

Hedda Wardemann ◽

Thomas Boehm ◽

Neil Dear ◽

Rita Carsetti

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Innate Immune ◽

Streptococcal Infections ◽

Wild Type ◽

Adaptive Immune ◽

Encapsulated Bacteria ◽

Increased Susceptibility

Splenectomized individuals are prone to overwhelming infections with encapsulated bacteria and splenectomy of mice increases susceptibility to streptococcal infections, yet the exact mechanism by which the spleen protects against such infections is unknown. Using congenitally asplenic mice as a model, we show that the spleen is essential for the generation of B-1a cells, a B cell population that cooperates with the innate immune system to control early bacterial and viral growth. Splenectomy of wild-type mice further demonstrated that the spleen is also important for the survival of B-1a cells. Transfer experiments demonstrate that lack of these cells, as opposed to the absence of the spleen per se, is associated with an inability to mount a rapid immune response against streptococcal polysaccharides. Thus, absence of the spleen and the associated increased susceptibility to streptococcal infections is correlated with lack of B-1a B cells. These findings reveal a hitherto unknown role of the spleen in generating and maintaining the B-1a B cell pool.

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IL-21 Plus CpG ODN Induces Granzyme B-Dependent Induction of Apoptosis in CD5-Positive B Cells Including B-CLL Cells.

Blood ◽

10.1182/blood.v108.11.2823.2823 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2823-2823

Author(s):

Sue E. Blackwell ◽

Bernd Jahrsdoerfer ◽

James E. Wooldridge ◽

Jian Huang ◽

Melinda W. Andreski ◽

...

Keyword(s):

B Cells ◽

Cord Blood ◽

Granzyme B ◽

Lymphocytic Leukemia ◽

Cpg Odn ◽

T And B Cells ◽

B1 Cells ◽

Lymphocyte Populations

Abstract Interleukin 21 (IL-21), a recently discovered cytokine with structural homology to IL-2, IL-4 and IL-15, has pleiotropic effects on lymphocyte populations including NK, T and B cells and is currently undergoing early clinical evaluation. We explored the effect of the combination of IL-21 and immunostimulatory CpG ODN on B chronic lymphocytic leukemia (B-CLL), and other CD5-positive B cells. IL-21 plus CpG ODN were synergistic in their ability to induce apoptosis of the B-CLL cells, and also induced production and secretion of granzyme B from the B-CLL cells. B-CLL cells treated with IL-21 and CpG ODN were capable of inducing apoptosis of untreated autologous B-CLL cells. This bystander killing was inhibited by anti-granzyme B antibodies. The effect was observed in all cases of CD5-positive B-CLL, but not in CD5-negative B-CLL samples. IL-21 plus CpG ODN also induced granzyme B production and apoptosis of benign CD5-positive B1 cells obtained from umbilical cord blood. In contrast, the number of CD5-negative B2 cells increased in the same samples during in vitro culture, resulting in a decreased ratio of CD5-positive to CD5-negative cord blood B cells (Fig. 1). Our results indicate the combination of IL-21 and CpG ODN is able to induce apoptosis of both benign and malignant CD5-positive B cells. Given the suspected role of B1 cells in autoimmune diseases, our findings could have important implications for the understanding of their pathogenetic mechanisms. These results might also open new avenues for the development of novel therapies for both autoimmune dieseases and CD5-positive B-CLL. Figure 1. IL- 21 and CpG ODN therapy selectively eliminates CD5 positive B cells in cord blood. Figure 1. IL- 21 and CpG ODN therapy selectively eliminates CD5 positive B cells in cord blood.

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