Lymphoid tissue inducer-A divergent member of the ILC family

Abstract

Innate lymphoid cells (ILCs) that are capable of producing effector cytokines reminiscent of CD4⁺ T helper (Th) cells during infections and tissue inflammations have drawn much attention in the immunology field in recent years. Within the ILCs, the lymphoid tissue inducer (LTi) cells that play a critical role in lymphoid organogenesis were identified long before the establishment of the ILC concept. LTi cells, developed and functioning mainly at the fetal stage, and LTi-like cells, presumably generated during the adulthood, are regarded as a subset of type 3 ILCs (ILC3s) because they express the ILC3 lineage-defining transcription factor RORγt, and like other ILC3s, can produce an ILC3 signature cytokine IL-22 and initiate protective immune responses against extracellular bacteria. However, LTi/LTi-like cells have a unique gene expression pattern, and they develop from a progenitor that is distinct from the progenitor of all other ILCs and the progenitor of conventional natural killer (cNK) cells. There are also several other unique features of LTi/LTi-like cells comparing to non-LTi ILC3s. In addition to their classical function in lymphoid organogenesis, LTi/LTi-like cells also have specialized functions in association with the adaptive immune system, which include their effects on T and B cell development, activation and function. In this review, we summarize these specific features of LTi/LTi-like cells and propose that these cells should be considered as a separated innate lymphoid lineage in parallel with other non-LTi ILCs and cNK cells.

Keywords: Adaptive immune system; Cell development and differentiation; Cell-cell interaction; Innate lymphoid cell; Lymphoid tissue inducer; Natural killer; T helper cell; Transcriptional regulation.

Figure 1. Development and differences of fetal and adult LTi cells

In the fetal stage, LTi cells are developed from their progenitors in the fetal liver. LTi progenitor cells are featured by their high expression of integrin α₄β₇, IL-7Rα and RORγt. Other molecules such as CCR6, TRANCE and CXCR5 are also expressed by these progenitors. The progenitor cells then migrate to other organs such as fetal spleen, small intestine and thymus, where they further mature and start to express lymphtoxin α₁β₂ (LTα₁β₂) and IL-22. In the adult stage, LTi cells (or LTi-like cells) are developed from the progenitors in the bone marrow. These progenitors still express high levels of integrin α₄β₇ and IL-7Rα, but relatively low levels of RORγt. Gene expression in mature adult LTi-like cells are very similar to that in fetal LTi cells, except that adult LTi cells additionally express OX40L and CD30L.

Figure 2. Similarities and differences between the development of innate and adaptive lymphoid system

The development of innate lymphocytes and T cells shows certain similarities. At mature stage, CD4⁺ T cells and ILCs produce similar sets of effector cytokines, while CD8⁺ T cells and cNK cells exhibit cytotoxic activities. In the innate lymphoid system, the development of LTi cells is distinct from other ILCs and cNK cells though they all generated from an early innate lymphocyte progenitor (EILP). The non-LTi ILCs are generated from an PLZF-expressing common progenitor, ILCP, while LTi cells developed from their own progenitor which depends on the master transcription factor RORγt. At mature stage, while non-LTi ILCs show plasticity under certain circumstances similar to what have been observed in differentiated CD4⁺ T cells, LTi cells are relatively stable.

Figure 3. Role of LTi cells in secondary lymphoid structure organogenesis

In the fetal stage, LTi cells will entry the lymph nodes or Peyer’s patches anlagen through the interaction between integrin α₄β₇ and MAdCAM-1 on the HEVs. CXCL13 secreted by LTo cells will also help to recruit LTi cells through interact with CXCR5 on them. Then LTi cells start to express lymphotoxin α₁β₂ (LTα₁β₂) and engage with the stromal cells expressing its receptor LTβR. This interaction will stimulate the stromal cells to upregulate TRANCE, CXCL13, CCL19, CCL21, MAdCAM-1, VCAM-1, and ICAM-1, which feedback on LTi cells to enhance its LTα₁β₂ expression and recruit more LTi as well as T and B cells in to the anlagen site.

Figure 4. Interactions between LTi cell and T or B cells in the adaptive immune system

LTi cells can affect development and functions of T and B cells in the adaptive immune system through multiple mechanisms. They interact with the mTECs through RNAK/TRANCE interaction and thus induce the expression of AIRE, which is critical for T cell central tolerance. LTi cells can also directly regulate the effector T cell responses through antigen presentation by MHC-II. The adult LTi-like cells specifically express OX40L and CD30L, which may promote the survival of memory CD4⁺ T cells. The same mechanism may be responsible for the survival of memory follicular T helper (Tfh) cells and maintenance of memory antibody responses. In addition, LTi cells may promote antibody production by B cells through both T-dependent and -independent manners. Antigen presentation and cytokine secretion to Tfh cells from LTi cells can enhance B cell responses. Alternatively, LTi cells may directly activate B cell through BAFF, CD40L, DLL1 and APRIL expression. TNF, lymphotoxin (LT), and GM-CSF expression by LTi can also activate B cells through marginal reticular cells (MRC) and neutrophils.