Typically naïve T cells encounter antigens in secondary lymphoid organs such as the LNs. Upon activation, they rapidly proliferate and differentiate into either effector or memory T cells. Effector T cells promptly migrate to inflamed tissues to assist with pathogen elimination. In contrast, memory T cells do not have immediate effector function, but persist after infection has been cleared and recirculate in the bloodstream, acting as a surveillance system in case of secondary challenge with the same pathogen, when they can provide immediate protection [98]. Initially, the memory T cell population was divided into two subtypes of cells, central memory T (TCM) and effector memory T (TEM) cells, both of which recirculate between the
blood, LNs and tissue after pathogen clearance. They are distinguished by the expression of CCR7, a chemokine receptor which directs cell homing to secondary lymphoid organs [160]. Resting TCM cells express high levels of CCR7 and CD62L, and are more sensitive to antigenic
stimulation than naïve T cells. Upon encountering cognate antigen, they rapidly proliferate to repopulate the memory T cell population, and can then differentiate into TEM cells. In contrast,
resting TEM cells lack CCR7 and express CD44, in addition to an array of surface markers and
chemokine receptors which allow them to migrate to inflamed tissues during infection [160, 161]. The TEM cell population can be subdivided into Th1-type and Th2-type TEM cells. Th1-type
TEM cells are characterised by expression of CXCR3 and CCR5, and production of IFN-γ upon
encountering cognate antigen [162]. In contrast, Th2-type TEM cells typically express high levels
of CCR4, and produce IL-4 when activated. TCM cells can also be classified based on expression
of chemokine receptors. Similarly, CXCR3+ TCM represent pre-Th1 type TEM, and CCR4+ TCM cells,
pre-Th2 type TEM cells [162].
In recent years, a third subtype of memory T cell was identified. In contrast to TEM and TCM
cells, these resident memory T (TRM) cells remain localised in the tissues after infection has
been cleared and do not recirculate to the bloodstream and secondary lymphoid organs. Indeed, TRM cells have been shown to be present in tissues at many barrier sites of the body,
including the skin [163, 164], gut [165, 166] and lung [167, 168]. Furthermore, these cells have also been found at non-barrier sites within the body, including the brain [169], kidneys [170] and heart [171]. Although TRM cells are distinct from TEM cells, they do share a number of
features including high expression of CD44, low expression of CD62L and CCR7, and the ability to produce cytokines [172]. CD69 is the primary marker used to identify TRM cells as all that
have been discovered so far express this C-type lectin. CD69 enables cell retention in tissues by downregulating surface expression of the sphingosine-1-phosphate receptor 1, which directs migration to the blood [173, 174]. CD103 expression on TRM cells has also been described
during infection of the intestines and lungs [175, 176]. However, expression of this integrin appears to be flexible, with reports of TRM cells lacking CD103 in the liver [168] and secondary
lymphoid organs [177]. Both CD4+ and CD8+ TRM cells have been identified, however, CD8+ TRM
cells and their functions have been described in greater detail. The reason for this is the majority of studies on TRM cells to date have utilised viral models of infection, where they were
originally identified [165, 178], and as viral infection typically generates substantially more CD8+ than CD4+ T cells, this focus has led to a large knowledge gap between the two subtypes. The role TRM cells play in protecting against infectious diseases is still being elucidated, but
there are several reports that CD8+ and CD4+ TRM cells are protective against secondary viral
infection in various tissues, including the lungs and skin of mice [178, 179]. Indeed, i.n. challenge with a sublethal dose of influenza virus resulted in the robust recruitment of CD8+CD103+ TRM cells, in addition to CD8+ TEM and TCM cells, in the lungs of mice [179].
Furthermore, these mice were protected from subsequent lethal i.n. challenge with influenza virus. In contrast, while intraperitoneal (i.p.) immunisation with a sublethal dose of influenza virus similarly generated robust levels of CD8+ TEM and TCM in the lungs, no CD103+ TRM cells
were induced and these mice were not protected from lethal infection [179]. Furthermore,
mice during viral infection, and that these cells confer protection against infection [167, 180]. In addition to their induction following infection, there are reports that TRM cells are expanded
following vaccination. Indeed, Connor and colleagues demonstrated that Bacillus Calmette- Guérin (BCG) vaccination recruits TRM cells to the lungs, and showed that these CD4+ TRM cells
were sufficient to confer protection against BCG infection [181].
Tailoring vaccines to promote the development and maintenance of these protective resident cells could be an ideal strategy to promote long-term immunity, however, TRM cells have been
implicated in the development of autoimmune conditions including psoriasis [182, 183], contact dermatitis [184] and inflammatory bowel disease [185]. More studies need to be performed to fully elucidate the mechanisms involved in rendering these cells pathogenic.