Tissue-Resident Lymphocytes Across Innate and Adaptive Lineages

Abstract

Lymphocytes are an integral component of the immune system. Classically, all lymphocytes were thought to perpetually recirculate between secondary lymphoid organs and only traffic to non-lymphoid tissues upon activation. In recent years, a diverse family of non-circulating lymphocytes have been identified. These include innate lymphocytes, innate-like T cells and a subset of conventional T cells. Spanning the innate-adaptive spectrum, these tissue-resident lymphocytes carry out specialized functions and cross-talk with other immune cell types to maintain tissue integrity and homeostasis both at the steady state and during pathological conditions. In this review, we provide an overview of the heterogeneous tissue-resident lymphocyte populations, discuss their development, and highlight their functions both in the context of microbial infection and cancer.

Keywords: cancer; conventional T cells; infection; innate lymphocyte; innate-like T cells; tissue resident.

Figure 1

Ontogeny of tissue-resident lymphocytes. All lymphocytes develop from the common lymphoid progenitor (CLP). In the bone marrow, an early innate lymphoid progenitor (EILp) can give rise to natural killer (NK) cells and innate lymphoid cells (ILCs). Whereas, the identity of an NK-restricted progenitor (NKp) remains unknown, a committed innate lymphoid cell progenitor (ILCp), which can give rise to all helper ILCs (ILChs), but not NK cells has been described. Less understood, ILCs with cytotoxic potential, or killer ILCs (ILCk) may arise from a hypothetical killer ILC progenitor (ILCkp) that have lost ILCh and NK potential. While ILCs are inherently tissue-resident, NK cells recirculate. Whether NK cells can acquire tissue-resident features remains unknown. Thus, the term tissue-resident NK (trNK) cells is better kept until such a possibility can be unequivocally ruled out. Beside innate lymphocytes, CLP also gives rise to T lineage-committed progenitors that complete their differentiation in the thymus. The vast majority of TCRαβ-expressing T cells undergo a double positive (DP) stage, during which MHC-based selection takes place. DP thymocytes bearing strongly self-reactive TCRs develop into unconventional intraepithelial lymphocyte (IEL) and natural killer T (NKT) cell lineages through agonist selection, while those with weakly self-reactive TCRs are diverted into single positive (SP) thymocytes, which subsequently give rise to conventional T (conv. T) cells. Whereas, IELs and NKT cells are naturally tissue-resident, conventional T cells recirculate but can become tissue-resident (T_RM) upon activation.

Figure 2

Cancer immunosurveillance by tissue-resident lymphocytes. Spontaneous oncogene-driven breast tumors are infiltrated by group 1 innate lymphocytes, conventional, and unconventional T cells. Parabiosis experiments revealed the tissue-resident nature of CD49a- and CD103-co-expressing lymphocytes, including the innate-like T cells (ILTCs), killer innate lymphoid cells (ILCks), and some conventional (Conv.) CD8⁺ T cells. In contrast, natural killer (NK) cells, PD1-expressing conventional CD8⁺ T cells recirculate through blood. Functionally, CD49a⁺CD103⁺ tissue-resident lymphocytes abundantly express lytic granules and can potently lyse transformed target cells. Despite their cytotoxicity, therapies targeting these tissue-resident populations are lacking while rapid advancement has been made to target conventional NK and T cells.