LTi-cells

LTi cells form a distinct lineage in the family of "innate lymphoid cells"(ILCs). ILCs are a heterogeneous collection of lymphocytes that lack antigen specificity(non-T, non-B cells) and potentially produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). Innate lymphoid cells are sessile cells. They do not circulate through the bloodstream and therefore belong to the local organ tissue where they are produced when needed.

ILCs are classified into group 1 (ILC1s), group 2 (ILC2s) or group 3 (ILC3s) (Doherty TA et al. 2019). They are important players in the innate immune system and perform a central role in the defense against infectious agents but are also associated with asthma, allergic rhinitis, chronic rhinosinusitis, food allergies and eosinophilic esophagitis (Bartemes KR et al. 2021).

LTi cells, which develop and function primarily in the fetal stage, and LTi-like cells, which presumably arise in adulthood, are considered 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 precursor that is distinct from the precursor of all other ILCs and the precursor of conventional natural killer (cNK) cells. LTi cells play a central role in lymphoid organogenesis (Zhong C et al. 2018).

The development of organized lymphoid tissue is described as a programmed process controlled by the interaction between mesenchymal lymphoid tissue organizer (LTo) cells and hematopoietic lymphoid tissue inducer (LTi) cells. It is likely that the initiation of lymph node development depends on LTi cell-mediated activation of lymphatic endothelial cells (LECs). The involvement of mesenchymal stromal cells is a subsequent event. Pharmacologically enforced interaction between Lti cells and LECs has been shown to promote ectopic LN formation (Onder L et al.2017).

In addition to their classical function in lymphoid organogenesis, LTi/LTi-like cells also have specialized functions related to the adaptive immune system that include their effects on T and B cell development, activation, and function. Thus, LTi cells share a pro-inflammatory profile with Th17 cells (Cherrier M et al.2012; Miller D et al. 2018).

Neo-genesis of lymphoid tissue: During fetal life, LTi cells are the first white blood cells. Thus, the nuclear hormone receptor RORgamma(t) is expressed exclusively in LTi cells. RORgamma(t+) LTI cells deliver essential factors, of which lymphotoxin-alpha1beta2 is required for activation of the mesenchyme in lymph node and Peyer's patch systems. The so-called lymphoid tissue organizer cells (LTo) play an important role in the formation of lymphoid tissue. These are undifferentiated mesenchymal cells. The LTo cells are activated by contact:

This early LTi-cell-mediated activation of the lymphoid and the mesenchyme of Peyer's plaques- provides the necessary platform for the later development of mature lymphoid tissues.( Eberl G et al 2004).

As soon as the infant's intestine is colonized with microbes after birth, the development of the lymphoid tissue undergoes a further activation and differentiation spurt. Especially in the intestinal mucosa tertiary lymphoid organs are formed by contact with the intestinal flora. Lymphoid tissue inducer (LTi) cells are associated with the early development of lymph nodes and Peyer's pllaques ( Eberl G et al. 2004).

Thus, the development of Peyer's plaques and lymph nodes necessitates the interaction between CD4+ CD3- IL-7Ralpha+ lymphoid tissue inducer (LTi) and VCAM-1+ organizer cells.

Of note, the role of IL-7, local IL-7 overexpression also leads to the formation of multiple organized ectopic lymph nodes and cecal patches. Therefore, IL-7 may regulate the formation of both normal and ectopic lymphoid organs by controlling LTi cell number.( Meier D et al. 2007).

LTi cells further induce the expression of AIRE. the autoimmune regulatory gene. This occurs via lymphotoxin α4β7 and RANKL signaling. LTi cells also facilitate memory CD4 + T cell survival and therefore memory immune responses within newly formed lymph nodes. Members of the TNF superfamily OX40L and CD30L, which signal to CD4 + T cells, play a role in this.

1. Bartemes KR et al (2021) Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s. J Allergy Clin Immunol 147: 1531-1547.
2. Cherrier M et al.(2012) The development of LTi cells. Curr Opin Immunol 24:178-83
3. Doherty TA et al. (2019) Airway innate lymphoid cells in the induction and regulation of allergy. Allergol Int 68: 9-16.
4. Eberl G et al (2004) An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 5:64-73
5. Meier D et al (2007) Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26: 643-54.
6. Miller D et al (2018) Innate lymphoid cells in the maternal and fetal compartments. Front Immunol 9:2396.
7. Onder L et al.(2017) Lymphatic endothelial cells control initiation of lymph node organogenesis. Immunity 47(1):80-92.
8. Zhong C et al. (2018) Lymphoid tissue inducer-A divergent member of the ILC family. Cytokine Growth Factor Rev 42:5-12.