Role of group 3 innate lymphoid cells in antibody production

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Highlights

Innate lymphoid cells (ILCs) constitute a heterogeneous family of effector lymphocytes of the innate immune system that mediate lymphoid organogenesis, tissue repair, immunity and inflammation. The initial view that ILCs exert their protective functions solely during the innate phase of an immune response has been recently challenged by evidence indicating that ILCs shape adaptive immunity by establishing both contact-dependent and contact-independent interactions with multiple hematopoietic and non-hematopoietic cells, including B cells. Some of these interactions enhance antibody responses both systemically and at mucosal sites of entry.

Introduction

Innate lymphoid cells (ILCs) include developmentally related groups of helper-like cells of the innate immune system that functionally mirror well-defined subsets of CD4+ T helper (TH) cells [1, 2]. Some of the effector molecules expressed by ILCs are known modulators of adaptive antibody responses emerging from T cell-dependent (TD) or T cell-independent (TI) pathways of B cell activation. This review discusses how group 3 ILC modulates homeostasis and antibody production in systemic and mucosal lymphoid tissues.

Section snippets

Phenotype and function of ILCs

Multiple subsets of ILCs emerge from a common lymphoid progenitor through a developmental pathway initiated by bone marrow or fetal liver stem cells. This pathway is dictated by signals from common cytokine receptor γ-chain and various transcription factors, including ID2, nuclear factor interleukin-3 regulated (NFIL3) and GATA3 [3, 4, 5, 6]. Despite their phenotypic and functional heterogeneity, ILCs share multiple properties, including lymphoid morphology, absence of common lineage-specific

Role of ILC3 in lymphoid organ development

ILC3 form a heterogeneous family of developmentally related lymphoid populations that rely on the cytokine IL-7 and the transcription factor RORγt for their differentiation [15, 19, 20, 21]. LTi cells are prototypic members of the ILC3 family [22]. These cells were first described some 20 years ago as fetal CD4+CD3 lymphocytes inhabiting the anlagen of mouse lymph nodes and embryonic Peyer's patches (PPs) [23]. Subsequent studies demonstrated that LTi cells are essential for the development of

Role of ILC3 in homeostasis and immunity

Besides promoting the development, maintenance and repair of peripheral lymphoid tissues, ILC3 maintain gut homeostasis in two ways: by preserving the integrity of intestinal epithelial cells (IECs) and by segregating commensal bacteria in the intestinal lumen [15, 17, 34, 35, 36]. These effects largely rely on ILC3 secretion of powerful IEC-stimulating cytokines, namely IL-22 [17, 35, 36]. Indeed, depletion of ILC3 causes systemic inflammation by inducing mucosal translocation and peripheral

Role of ILC3 in systemic antibody responses

Growing evidence indicates that, besides mediating innate immunity, ILC3 regulate adaptive immune responses (Figure 1), including antibody production by B cells [1, 29••, 43••, 44••]. After recognizing antigen through transmembrane immunoglobulin M (IgM) and IgD antibodies generally referred to as B cell receptor (BCR), mature naïve B cells usually follow a TD pathway to generate humoral immunity [45]. This pathway involves cognate interactions of B cells with effector CD4+ T follicular helper

Role of ILC3 in mucosal antibody responses

Host-commensal mutualism involves intestinal release of massive amounts of non-inflammatory IgA antibodies [60]. Intestinal IgA predominantly emerges from a TD pathway that unfolds in the follicles of PPs, a compartment of the gut-associated lymphoid tissue that develops during fetal life in response to LTi cells [60]. After post-natal intestinal colonization by commensal bacteria, PPs develop a GC reaction involving cognate interaction of follicular B cells with TFH cells that emerge from

Conclusions

A hallmark of ILC3 relates to their expression of the TNF family members LT, TNF, OX40L, CD30L, LIGHT, RANKL, BAFF, APRIL and CD40L [28, 29••, 50]. All of these molecules play an essential role in lymphoid organogenesis, B-T segregation and B or T cell activation, diversification, differentiation and intestinal homing. Activated ILC3 also release IL-2, IL-6, IL-10, IL-17 and IP-10 [44••], which contribute to the initiation or modulation of T and B cell responses. Furthermore, activated ILC3

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

Supported by European Research Council under the European Union's Seven Framework Programme (FP7/2007-2013)/ERC grant agreement n° 294561, Ministerio de Ciencia e Innovación grant SAF2011-25241, and US National Institutes of Health grants R01 AI57653, U01 AI95613, P01 AI61093 and U19 096187 to A.C.; and by a Juan de la Cierva post-doctoral fellowships to G.M.

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