Complementary Role of CD4+ T Cells in Response to Pneumococcal Polysaccharide Vaccines in Humans

Bacterial pathogens expressing capsular polysaccharides are common causes of mucosal infections (pneumonia, intestinal), as well as often fatal, invasive infections (meningitis, bloodstream infections) in children and adults worldwide. These chemically simple but structurally complex carbohydrate structures on the bacterial surface confer resistance to recognition and clearance by the immune system through a range of mechanisms. Such recognition of capsular polysaccharides may be reduced by their limited ability to directly stimulate B cells and the T cells that may facilitate these humoral responses. The capsules may promote the evasion of complement deposition and activation and may sterically shield the recognition of other subjacent protein antigens by innate factors. Antibodies to capsular polysaccharides, elicited by infection and vaccines, may overcome these obstacles and facilitate bacterial agglutination at mucosal surfaces, as well as the opsonization and clearance of these organisms in tissues and the systemic compartment. However, the immunogenicity of these antigens may be limited by their lack of direct recognition by T cells ("T-independent" antigens) and their restricted ability to generate effective memory responses. In this review, we consider the mechanisms by which polysaccharides may initiate B cell responses and specific antibody responses and the role of T cells, particularly CD4+ follicular helper (TFH) cells to support this process. In addition, we also consider more recent counterintuitive data that capsular polysaccharides themselves may bind major histocompatibility antigen HLA class II to provide a more physiologic mechanism of T cell enhancement of B cell responses to capsular polysaccharides. Defining the contributions of T cells in the generation of effective humoral responses to the capsular polysaccharides will have important implications for understanding and translating this immunobiology for the development of more effective vaccines, to prevent the morbidity and mortality associated with these common mucosal and invasive pathogens in populations at risk.

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The allogeneic bisection of carrier-specific enhancement of monoclonal B-cell responses.

Journal of Experimental Medicine ◽

10.1084/jem.142.5.1165 ◽

1975 ◽

Vol 142 (5) ◽

pp. 1165-1179 ◽

Cited By ~ 42

Author(s):

S K Pierce ◽

N R Klinman

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Immunoglobulin Class ◽

Cell Responses ◽

Cell Clones ◽

Ia Antigens ◽

Collaborative Interactions ◽

B Cell Responses

The ability of T cells to enhance the response of syngeneic and allogeneic B cells to thymus-dependent hapten-carrier conjugates was analyzed. This analysis was carried out on individual primary B cells in splenic fragment cultures derived from irradiated reconstituted mice. This system has several advantages: (a) the response of the B cells is entirely dependent on carrier priming of the irradiated recipient; (b) this B-cell response can be quantitated in terms of the number of responding cells; and (c) very small B-cell responses can be readily detected and analyzed. The results indicate that the majority of hapten-specific B cells were stimulated in allogeneic and syngeneic recipients only if these recipients were previously carrier primed. The number of B cells responding in carrier-primed allogeneic recipients was 60-70% of that in syngeneic carrier-primed recipients. The antibody-forming cell clones resulting from B cells stimulated in the allogeneic environment produced small amounts of antibody and antibody solely of the IgM immunoglobulin class, while the larger responses in syngeneic recipients were predominantly IgG1 or IgM plus IgG1. The capacity of collaborative interactions between carrier-primed T cells and primary B cells to yield IgG1 antibody-producing clones was shown to be dependent on syngeny between these cells in the H-2 gene complex. It is concluded that: (a) B cells can be triggered by T-dependent antigens to clone formation through collaboration with T cells which differ at the H-2 complex as long as these T cells recognize the antigen; (b) the immunoglobulin class produced by the progeny of stimulated B cells generally depends on the nature of the stimulatory event rather than the nature of the B cell itself; and (c) stimulation to IgG1 production is dependent on syngeny between the collaborating T and B cells probably within the Ir-1A region. The role of the Ia antigens in the formation of IgG1-producing clones is not yet clear; Ia identity could permit IgG1 production or, conversely, nonidentity of Ia could induce all allogeneic interactions which prohibit IgG1 production.

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Blockade of LAG-3 in PD-L1-Deficient Mice Enhances Clearance of Blood Stage Malaria Independent of Humoral Responses

Frontiers in Immunology ◽

10.3389/fimmu.2020.576743 ◽

2021 ◽

Vol 11 ◽

Author(s):

Raquel Furtado ◽

Laurent Chorro ◽

Natalie Zimmerman ◽

Erik Guillen ◽

Emily Spaulding ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Blood Parasites ◽

Natural Immunity ◽

Inhibitory Receptors ◽

Chronic Infections ◽

Cell Functions ◽

Cell Responses ◽

B Cell Responses ◽

Humoral Responses

T cells expressing high levels of inhibitory receptors such as PD-1 and LAG-3 are a hallmark of chronic infections and cancer. Checkpoint blockade therapies targeting these receptors have been largely validated as promising strategies to restore exhausted T cell functions and clearance of chronic infections and tumors. The inability to develop long-term natural immunity in malaria-infected patients has been proposed to be at least partially accounted for by sustained expression of high levels of inhibitory receptors on T and B lymphocytes. While blockade or lack of PD-1/PD-L1 and/or LAG-3 was reported to promote better clearance of Plasmodium parasites in various mouse models, how exactly blockade of these pathways contributes to enhanced protection is not known. Herein, using the mouse model of non-lethal P. yoelii (Py) infection, we reveal that the kinetics of blood parasitemia as well as CD4+ T follicular helper (TFH) and germinal center (GC) B cell responses are indistinguishable between PD-1-/-, PD-L1-/- and WT mice. Yet, we also report that monoclonal antibody (mAb) blockade of LAG-3 in PD-L1-/- mice promotes accelerated control of blood parasite growth and clearance, consistent with prior therapeutic blockade experiments. However, neither CD4+ TFH and GC B cell responses, nor parasite-specific Ab serum titers and capacity to transfer protection differed. We also found that i) the majority of LAG-3+ cells are T cells, ii) selective depletion of CD4+ but not CD8+ T cells prevents anti-LAG-3-mediated protection, and iii) production of effector cytokines by CD4+ T cells is increased in anti-LAG-3-treated versus control mice. Thus, taken together, these results are consistent with a model in which blockade and/or deficiency of PD-L1 and LAG-3 on parasite-specific CD4+ T cells unleashes their ability to effectively clear blood parasites, independently from humoral responses.

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The Role of Vav Proteins in B Cell Responses

Advances in Experimental Medicine and Biology - Lymphocyte Activation and Immune Regulation IX ◽

10.1007/978-1-4615-0757-4_4 ◽

2002 ◽

pp. 29-34 ◽

Cited By ~ 4

Author(s):

Martin Turner

Keyword(s):

B Cell ◽

Cell Responses ◽

B Cell Responses

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Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses

Cell Reports ◽

10.1016/j.celrep.2020.03.007 ◽

2020 ◽

Vol 30 (12) ◽

pp. 4110-4123.e4 ◽

Cited By ~ 3

Author(s):

Reza Nadafi ◽

Catarina Gago de Graça ◽

Eelco D. Keuning ◽

Jasper J. Koning ◽

Sander de Kivit ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Regulatory T Cells ◽

B Cell ◽

Stromal Cells ◽

Cell Responses ◽

B Cell Responses ◽

And Control ◽

Lymph Node Stromal Cells

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Fas Expression on Antigen-Specific T Cells Has Costimulatory, Helper, and Down-Regulatory Functions In Vivo for Cytotoxic T Cell Responses but Not for T Cell-Dependent B Cell Responses

The Journal of Immunology ◽

10.4049/jimmunol.181.9.5912 ◽

2008 ◽

Vol 181 (9) ◽

pp. 5912-5929 ◽

Cited By ~ 17

Author(s):

Irina Puliaeva ◽

Roman Puliaev ◽

Andrei Shustov ◽

Mark Haas ◽

Charles S. Via

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Cell Responses ◽

B Cell Responses ◽

Cytotoxic T Cell Responses ◽

Regulatory Functions

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Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

Frontiers in Neurology ◽

10.3389/fneur.2020.607766 ◽

2020 ◽

Vol 11 ◽

Author(s):

Austin Negron ◽

Olaf Stüve ◽

Thomas G. Forsthuber

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Responses ◽

Memory B Cells ◽

Lymphoid Follicles ◽

Cell Responses ◽

B Cell Responses

While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.

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