Role of CD28 in Polyclonal and Specific T and B Cell Responses Required for Protection against Blood Stage Malaria

Although most vaccines against blood stage malaria in development today use subunit preparations, live attenuated parasites confer significantly broader and more lasting protection. In recent years, Plasmodium genetically attenuated parasites (GAPs) have been generated in rodent models that cause self-resolving blood stage infections and induce strong protection. All such GAPs generated so far bear mutations in housekeeping genes important for parasite development in red blood cells. In this study, using a Plasmodium berghei model compatible with tracking anti–blood stage immune responses over time, we report a novel blood stage GAP that lacks a secreted factor related to histamine-releasing factor (HRF). Lack of HRF causes an IL-6 increase, which boosts T and B cell responses to resolve infection and leave a cross-stage, cross-species, and lasting immunity. Mutant-induced protection involves a combination of antiparasite IgG2c antibodies and FcγR+ CD11b+ cell phagocytes, especially neutrophils, which are sufficient to confer protection. This immune-boosting GAP highlights an important role of opsonized parasite-mediated phagocytosis, which may be central to protection induced by all self-resolving blood stage GAP infections.

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

Vaccines ◽

10.3390/vaccines7010018 ◽

2019 ◽

Vol 7 (1) ◽

pp. 18 ◽

Cited By ~ 4

Author(s):

Vibha Jha ◽

Edward N. Janoff

Keyword(s):

T Cells ◽

B Cell ◽

Bloodstream Infections ◽

Capsular Polysaccharides ◽

Protein Antigens ◽

Cell Responses ◽

Populations At Risk ◽

B Cell Responses ◽

Humoral Responses

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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