Conventional T cells in the mucosa can be classified as either major histocompatibility class II (MHC II)-restricted and αβ T cell receptor (TCR)-expressing CD4+ T cells (helper T cells, or TH cells) or MHC I-restricted and αβ TCR-expressing CD8αβ+ T cells. These T cells develop in the thymus and migrate into mucosal effecting sites after encountering antigen stimuli in lymphoid tissues.2,4 However, in the mucosa, another unique subset of T cells exists within the epithelial layer. These T cells express either αβ or γδ TCR and mostly express CD8αα homodimers but not CD8αβ heterodimers, i.e., unconventional CD8αα+ αβ T cells and γδ T cells.
The mucosa is a cytokine-rich environment where ECs, macrophages, dendritic cells (DCs) and T cells produce various types of cytokines, such as transforming growth factor (TGF)-β, interleukin (IL)-6, IL-10 and IL-12.5 After TCR activation, naive T cells differentiate into different TH subsets depending on different cytokine milieu. These TH cells then exert either inflammatory or regulatory responses.6,7,8 During the past few decades, several TH subsets have been identified: TH1, TH2, TH17, TH22, TH9, follicular helper T (Tfh) cells and regulatory T (Treg) cells.6,9 These subsets are characterized by the production of different effector cytokines and the expression of distinct transcription factors (Figure 2). Here, we focus on TH cells and Treg cells.
After priming by APCs, naive T cells begin proliferating and differentiating. TH differentiation depends on the cytokine environment. TGF-β drives Treg cell generation; furthermore, in combination with IL-6 or IL-4, TGF-β also drives TH17 and TH9 cell differentiation, respectively. Cytokines initiate downstream signalling pathways to promote the expression of transcription factors such as the TH1 cell master transcription factor T-bet and the TH2 cell master transcription factor GATA3. These transcription factors are indispensable for their key roles in TH cell cytokine expression and TH cell function. APC, antigen presenting cell; IL, interleukin; INF, interferon; TGF, transforming growth factor; TH, T helper cell; Treg, regulatory T cell 1).
Innate lymphoid cells (ILCs) have emerged as a new family of innate counterparts of T helper lymphocytes. ILCs are derived from an Id2-dependent lymphoid cell progenitor cell population abundant at mucosal surfaces, and play a significant role as a first line of defense against pathogens as well as in immune homeostasis. ILCs rapidly respond to microbial and cytokine signals and are potent innate cellular sources of multiple pro-inflammatory and immunoregulatory cytokines 2). ILCs have also been shown to play a critical role in modulating adaptive immunity toward tolerance and/or protective immunity 3). There is considerable phenotypic and functional heterogeneity in the mature ILC family, and broadly three groups of ILCs (ILC1, ILC2, and ILC3) have been defined based on shared expression of surface markers, transcription factors, and effector cytokines 4). ILCs orchestrate acute inflammation to promote immunity to infection as well as promote the resolution of infection-mediated inflammation and damage of tissues in lungs and intestine 5). They have also been shown to promote the barrier function of lung epithelium and lung tissue homeostasis in multiple chronic infectious and inflammatory diseases of the respiratory tract. Lung tissue destruction and/or remodeling is a key process in the development of TB disease.
γδ T cells are a distinct subset of CD3+ T cells, which carry a T cell receptor encoded by Vγ and Vδ gene segments. They recognize unprocessed, non-peptide phosphate antigens in a non-MHC restricted manner 6) which express IFN-γ and IL-17 along with cytotoxic effector function 7). γδ T cells represent an early defense against pulmonary TB and serve as a link between innate and adaptive immunity.
Mucosa-associated invariant T (MAIT) cells are prevalent in blood and mucosal sites in humans. They are unique innate cytotoxic T cells that emerge from the thymus as effectors, and thus act as immediate effectors in response to pathogens. MAIT cells have a limited T cell receptor repertoire, act in a non-classical MR1-restricted manner, get stimulated by vitamin B metabolites common in bacteria and yeast, and respond to host cells infected with bacterial pathogens with cytokine production and cytotoxicity, without prior priming and stimulation 8). MAIT cells have been shown to produce IFN-γ and TNF-α in response to Mtb-infected cells and also induce target cell lysis through secretion of cytotoxic granules 9).
As discussed earlier, both the magnitude and breadth of the T cell response is of importance. However, it should be noted that simply determining the magnitude in the blood is not always valuable, as vaccine efficacy depends also on the type of memory T cell and its location. For example, a direct association between protection and the frequency of the T cells in the circulation does not always exist 10) Actually, depending on the route of infection, T cells present in the mucosal surfaces or in the tissues (TEM and/or TRM) play a dominant role in controlling the infection, and sufficient numbers in these areas rather than in the circulation are likely required to form a robust frontline defense against, e.g., HIV-1 11)12)