The Mechanism of Splenic Invariant NKT Cell Activation Dictates Localization In Vivo

King, Irah L.; Amiel, Eyal; Tighe, Mike; Mohrs, Katja; Veerapen, Natacha; Besra, Gurdyal S.; Mohrs, Markus; Leadbetter, Elizabeth A.

doi:10.4049/jimmunol.1300299

Cited by 46 publications

(73 citation statements)

References 47 publications

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“…iNKT cells consolidate in the MZ and favor interactions with MZ B cells (40) which express a higher level of CD1d than all other APCs in the spleen (41), and iNKT cells cultured with MZ B cells proliferate more vigorously than iNKT cells mixed with follicular B cells (2). Given this previous work, we evaluated the possibility that activated iNKT cells preferentially expand innate MZ B cells.…”

Section: Discussionmentioning

confidence: 99%

“…We next considered that iNKT helper cells may partner with innate B cells that do not support humoral memory. Cognate antigen immunization localizes iNKT cells in the MZ (40), and MZ B cells express the highest levels of CD1d of any immune cell (41); therefore, we examined the influence of iNKT-cell help on MZ B cells. We found that mice receiving either NPαGalCer or NP-KLHαGalCer had expanded MZ B-cell populations at day 4, but only mice receiving NPαGalCer still had an expanded MZ B-cell population at day 8 (Fig.…”

Section: Noncognate Inkt Cell Help Induces Higher Numbers Of T Fh Celmentioning

confidence: 99%

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Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

Vomhof-DeKrey

Yates

Hägglöf

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Successful induction of B-cell activation and memory depends on help from CD4 + T cells. Invariant natural killer T (iNKT) cells (glycolipid-specific, CD1d-restricted innate lymphocytes) provide both cognate (direct) and noncognate (indirect) helper signals to enhance B-cell responses. Both forms of iNKT-cell help induce primary humoral immune responses, but only noncognate iNKT-cell help drives humoral memory and plasma cells. Here, we show that iNKT cognate help for B cells is fundamentally different from the help provided by conventional CD4 + T cells. Cognate iNKT-cell help drives an early, unsustained germinal center B-cell expansion, less reduction of T follicular regulatory cells, an expansion of marginal zone B cells, and early increases in regulatory IL-10-producing B-cell numbers compared with noncognate activation. These results are consistent with a mechanism whereby iNKT cells preferentially provide an innate form of help that does not generate humoral memory and has important implications for the application of glycolipid molecules as vaccine adjuvants.

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Section: Discussionmentioning

confidence: 99%

Section: Noncognate Inkt Cell Help Induces Higher Numbers Of T Fh Celmentioning

confidence: 99%

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

Vomhof-DeKrey

Yates

Hägglöf

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…At the steady state, iNKT cells are mainly located in the marginal zone of the spleen, strategically prepositioned in close contact with macrophages and DCs that capture blood-borne Ags flowing through the red pulp, with a scattered distribution in the red pulp and white pulp [41][42][43]. Upon αGalCer immunization, marginal zone DCs uptake and present αGalCer, and subsequently iNKT cells concentrate in the marginal zone and in bridging channels, where they rapidly produce cytokines [42,43]. This promotes the maturation of DCs that upregulate expression of CC chemokine receptor 7 and relocate into the T-cell zone of the white pulp [43].…”

Section: Mechanisms Of Inkt-cell-mediated B-cell Helpmentioning

confidence: 99%

“…Preclinical results highlight the efficacy and attractiveness of the use of vaccine containing αGalCer simply mixed with protein Ags derived from a variety of infectious pathogens, to activate noncognate B-cell help by iNKT cells and induce efficient protective humoral responses and long-lasting memory through mucosal and parenteral administration routes [43,[46][47][48][49].…”

Section: Noncognate Help By Inkt Cellsmentioning

confidence: 99%

“…Upon αGalCer immunization, marginal zone DCs uptake and present αGalCer, and subsequently iNKT cells concentrate in the marginal zone and in bridging channels, where they rapidly produce cytokines [42,43]. This promotes the maturation of DCs that upregulate expression of CC chemokine receptor 7 and relocate into the T-cell zone of the white pulp [43]. In the white pulp, DCs can enhance the induction of T FH cells, which then provide help to cognate B cells.…”

Section: Noncognate Help By Inkt Cellsmentioning

confidence: 99%

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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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A Designed α‐GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d‐iNKT Axis and CD11b‐Positive Monocytes/Macrophages

Zhao

et al. 2020

Advanced Science

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Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α ‐galactosylceramide ( α ‐GalCer, KRN7000), a well‐studied Th1‐polarizer, simultaneously induces helper T cell 2 (Th2)‐type responses, which is a major drawback for its clinical applications. Based on surflex‐docking computation, α ‐GalCer‐diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α ‐GalCer‐diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self‐activation, as reflected by tight binding of the T‐cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL‐12) and interferon‐ γ (IFN‐ γ ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1‐type cytokine profile ex vivo and in vivo. Different from KRN7000, α ‐GalCer‐diol markedly boosts the expansion of the CD11b + subpopulation and enhances IFN‐ γ content in CD11b + cells. These reinforced Th1‐type responses collectively endow α ‐GalCer‐diol more robust antitumor activity in a xenograft animal model using B16‐F10 melanoma cells. Together, the data demonstrate a new mechanism through which α ‐GalCer‐diol induces stronger Th1‐type responses by stimulating CD11b + leukocyte expansion and DC‐conducted CD1d‐restricted and TCR‐mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.

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The Mechanism of Splenic Invariant NKT Cell Activation Dictates Localization In Vivo

Cited by 46 publications

References 47 publications

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

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

A Designed α‐GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d‐iNKT Axis and CD11b‐Positive Monocytes/Macrophages

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