SAP expression in invariant NKT cells is required for cognate help to support B-cell responses

Detre, Cynthia; Keszei, Márton; Garrido-Mesa, Natividad; Kis-Tóth, Katalin; Castro, Wilson; Agyemang, Amma F.; Veerapen, Natacha; Besra, Gurdyal S.; Carroll, Michael; Tsokos, George C.; Wang, Ninghai; Leadbetter, Elizabeth A.; Terhorst, Cox

doi:10.1182/blood-2011-11-395913

Cited by 33 publications

(48 citation statements)

References 36 publications

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“…These data concur with a recent report describing an independently generated mouse strain harboring a targeted SAP allele. 18 Furthermore, they reveal that following completion of normal iNKT cell ontogeny, the deletion of SAP does not influence iNKT phenotype, persistence, or the ability to respond to DC-mediated presentation , proteins with homology to SAP that inhibit murine NK-cell natural cytotoxicity and cytokine production. 25 Thus, the SAP-dependent defects in killing are not due to the altered expression of these deathpromoting or inhibitory proteins.…”

Section: Statisticsmentioning

confidence: 99%

The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

Das¹,

Bassiri

Guan³

et al. 2013

Blood

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Section: Statisticsmentioning

confidence: 99%

The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

Das¹,

Bassiri

Guan³

et al. 2013

Blood

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“…Coordinate recognition of Ags in complex with CD1d and MHC II on the surface of DCs by iNKT cells and Th cells has been shown to result in an enhanced induction of the Th-cell response and enhanced delivery of classic T-cell help [38,39]. In addition, help by noncognate iNKT cells has been shown to require CD40 expression on B cells [38] -but not the expression of the T FH -cell-related molecule SLAM-associated protein by iNKT cells [40] -and was reported to occur also in splenectomized mice, ruling out the need for innate-like B cells, which reside in the spleen [38]. Overall, the αGalCer-induced, noncognate help by iNKT cells recapitulates the functions of adjuvants that activate the innate immune system to support adaptive immune responses.…”

Section: Noncognate Help By Inkt Cellsmentioning

confidence: 99%

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

2014

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T-cell help to B lymphocytes is one of the most important events in adaptive immune responses in health and disease. It is generally delivered by cognate CD4 + T follicular helper (T FH ) cells via both cell-to-cell contacts and soluble mediators, and it is essential for both the clonal expansion of antibody (Ab)-secreting B cells and memory B-cell formation. CD1d-restricted invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that rapidly respond to stimulation with specific lipid antigens (Ags) that are derived from infectious pathogens or stressed host cells. Activated iNKT cells produce a wide range of cytokines and upregulate costimulatory molecules that can promote activation of dendritic cells (DCs), natural killer (NK) cells, and T cells. A decade ago, we discovered that iNKT cells can help B cells to proliferate and to produce IgG Abs in vitro and in vivo. This adjuvant-like function of Ag-activated iNKT cells provides a flexible set of helper mechanisms that expand the current paradigm of T-cell-B-cell interaction and highlights the potential of iNKT-cell targeting vaccine formulations.Keywords: B-cell help r CD1d r T follicular helper cells r vaccines IntroductionThe production of neutralizing antibodies (Abs) by B cells represents a major parameter of host defense against infectious pathogens and is a key component of protective immune responses elicited by vaccines [1]. The innate and adaptive arms of the immune system are functionally separated, but seem to be highly coordinated to ensure an optimal outcome of immune responses. Although innate and adaptive immune cells are endowed with very distinct functions and timing of response, there are specialized lymphocyte subsets that straddle the two programs, and these cells have been defined as innate-like lymphocytes [2]. CD1d-rectricted invariant Vα14 natural killer T (iNKT) cells are one of the best characterized types of innate-like T lymphocytes, which display multiple effector functions upon activation [3]. Here, we review the mechanisms through which iNKT cells help B cells to promote Ab production and memory formation.Correspondence: Dr. Paolo Dellabona e-mail: dellabona.paolo@hsr.itThe TD and TI paradigm of the B-cell response B-cell responses are generally described as T-dependent (TD) or T-independent (TI), based on the requirement for T-cell help for Ab production. TD responses are induced by protein antigens (Ags) that are recognized by specific B cells in the presence of cognate T-cell help, which is provided by a specialized subset of CD4 + T helper (Th) cells called T follicular helper (T FH ) cells [4]. Ags reach the follicles, the B-cell zone of secondary lymphoid organs, and activate B cells upon binding to the specific B-cell receptors (BCRs [5]). This leads to Ag internalization, presentation of the processed Ag peptides into MHC class II (MHC II) molecules, and migration of the activated B cells to the border of the T-B-cell zone [4]. T FH cells are induced in the T-cell zone by dendritic cells (DCs) t...

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“…Moreover, primary iNKTFH cells expressing high levels of CXCR5 have been detected in human tonsils [55], implying that they are spontaneously induced by environmental Ags. The differentiation of iNKTFH and TFH cells share similar molecular requirements, as iNKTFH cells' formation and cognate help to B cells are abrogated in the absence of Bcl-6 or SAP expression, respectively [55,64]. Consistent with the requirement of CD28 mediated co-stimulation for TFH cells formation, also αGalCer immunization of Cd28 −/− mice does not result in iNKTFH cell differentiation [55].…”

Section: Cognate Inkt Cell Help For B Cellsmentioning

confidence: 69%

B Cell Help by CD1d-Rectricted NKT Cells

2015

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B cell activation and antibody production against foreign antigens is a central step of host defense. This is achieved via highly regulated multi-phase processes that involve a variety of cells of both innate and adaptive arms of the immune system. MHC class II-restricted CD4 + T cells specific for peptide antigens, which acquire professional follicular B cell helper functions, have been long recognized as key players in this process. Recent data, however, challenge this paradigm by showing the existence of other helper cell types. CD1d restricted NKT cells specific for lipid antigens are one such new player and can coopt bona fide follicular helper phenotypes. Their role in helping antigen-specific B cell response to protein antigens, as well as to the so called "help-less" antigens that cannot be recognized by T follicular helper cells, is being increasingly elucidated, highlighting their potential pathophysiological impact on the immune response, as well as on the design of improved vaccine formulations.

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SAP expression in invariant NKT cells is required for cognate help to support B-cell responses

Cited by 33 publications

References 36 publications

The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

B Cell Help by CD1d-Rectricted NKT Cells

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