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

Abstract

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...

NKT-dependent B-cell activation in Gaucher disease

“…However, it remains to be determined whether the B memory responses elicited by type II NKT cells are short lived, as seen in the case of type I NKT T FH . 8 These results are of great interest, as the authors report an increased frequency of LGL1-specific T cells in a mouse model of GD and in patients with GD (over 20-fold in mice and 3-fold in humans). Notably, the frequency of type I NKT in GD mice is significantly reduced, in agreement with data showing impairment in their selection in mouse models of lysosomal storage disorders.…”

“…5 Clinical relapse within several months has been documented after partial response to vemurafenib. 8 How long patients can be maintained after relapse from complete or partial remission before requiring additional therapy has yet to be reported. Thus far, other treatments for HCL that are associated with elimination of HCL MRD include cladribine alone, at least in a minority of cases, purine analogs combined with rituximab in a majority of cases, and the anti-CD22 recombinant immunotoxin moxetumomab pasudotox.…”

Innate-like lymphocytes in intestinal infections

“…iNKT cells mediate their effector function primarily through rapid cytokine release following activation [39], including both Th1 (IFN-γ and TNF-α), Th2 (IL-1, IL-4, and IL-13), and Th17 (IL-17, IL-22) cytokines [38, 41]. They have also been shown to enhance B cell responses through both cognate and noncognate mechanisms [42]. …”

B Cell Help by CD1d-Rectricted NKT Cells

“…Recently, however, it became clear that CD1d-restricted natural killer T (NKT) cells, a subset of lipid-specific T lymphocytes that display innate-effector functions, can also help B cell responses [3]. Both CD4 + T and…”

“…Several studies have shown that iNKT cells provide help to B cells, either directly or indirectly, with different outcomes [3]. Therefore, iNKT cells are considered as a bridge between innate and adaptive immune responses.…”