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Review
. 2018 Nov 27:9:2636.
doi: 10.3389/fimmu.2018.02636. eCollection 2018.

Tissue Adaptations of Memory and Tissue-Resident Gamma Delta T Cells (V体育官网)

Affiliations
Review

Tissue Adaptations of Memory and Tissue-Resident Gamma Delta T Cells

Camille Khairallah et al. Front Immunol. .

Abstract

Epithelial and mucosal barriers are critical interfaces physically separating the body from the outside environment and are the tissues most exposed to microorganisms and potential inflammatory agents. The integrity of these tissues requires fine tuning of the local immune system to enable the efficient elimination of invasive pathogens while simultaneously preserving a beneficial relationship with commensal organisms and preventing autoimmunity. Although they only represent a small fraction of circulating and lymphoid T cells, γδ T cells form a substantial population at barrier sites and even outnumber conventional αβ T cells in some tissues. After their egress from the thymus, several γδ T cell subsets naturally establish residency in predetermined mucosal and epithelial locations, as exemplified by the restricted location of murine Vγ5+ and Vγ3Vδ1+ T cell subsets to the intestinal epithelium and epidermis, respectively VSports手机版. Because of their preferential location in barrier sites, γδ T cells are often directly or indirectly influenced by the microbiota or the pathogens that invade these sites. More recently, a growing body of studies have shown that γδ T cells form long-lived memory populations upon local inflammation or bacterial infection, some of which permanently populate the affected tissues after pathogen clearance or resolution of inflammation. Natural and induced resident γδ T cells have been implicated in many beneficial processes such as tissue homeostasis and pathogen control, but their presence may also exacerbate local inflammation under certain circumstances. Further understanding of the biology and role of these unconventional resident T cells in homeostasis and disease may shed light on potentially novel vaccines and therapies. .

Keywords: adaptive γδ T cells; barrier infections; innate γδ T cells; memory γδ T cells; resident γδ T cells. V体育安卓版.

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Figures

Figure 1
Figure 1
Inflammation-induced dermal memory γδ T cells sensitize mice to imiquimod-induced psoriasis. Topical skin exposure of naïve mice to the TLR7/8 ligand imiquimod (IMQ) activates regional dendritic cells (Langerhans cells or dermal DCs) which migrate to the draining lymph nodes and present antigens to Vγ2Vδ4+ T cells. Activated γδ T cells proliferate, acquire an effector/memory CD44hi CD27 CD62L phenotype and upregulate several migration molecules favoring their egress from the lymph nodes (S1P1) and homing to the inflamed and resting skin dermis (CCR2 and cutaneous lymphocyte-associated antigen or CLA), where the cells establish memory. Secondary IMQ skin application at the same or a distant site leads to the local proliferation and activation of dermal memory Vγ2Vδ4+ T cells, which produce large amount of IL-17A/F and promote the recruitment of neutrophils and thereby exacerbate skin inflammation.
Figure 2
Figure 2
Memory γδ T cell response to pulmonary Bordetella pertussis infection. Upon primary intranasal infection with Bordetella pertussis (B. pertussis), Vγ2Vδ4+ T cells are activated by B. pertussis antigen-presenting dendritic cells either in the draining lymph nodes or directly in the lung tissue. Activated γδ T cells expand, display a CD44+ and CD103+CD69+/− activated resident memory phenotype and remain at an elevated number in the lungs after bacterial clearance. Secondary exposure to B. pertussis induces a recall expansion of memory Vγ2Vδ4+ T cells in the lung tissue and a protective and robust IL-17A response leading to an enhanced pathogen clearance.
Figure 3
Figure 3
Listeria monocytogenes elicits a multifunctional protective memory response from fetal γδ T cells. Shortly after oral infection, the foodborne pathogen Listeria monocytogenes (L. monocytogenes) crosses the intestinal barrier and migrates to the mesenteric lymph nodes (MLNs). Whether L. monocytogenes reaches the MLNs extracellularly or is carried intracellularly by migratory intestinal dendritic cells is yet unclear. Colonization of the MLNs leads to the expansion of a population of semi-invariant Vγ4Vδ1+ T cells characterized by a CD44hi CD27 phenotype and the rare ability to co-produce both IL-17A and IFNγ, in a process that would likely involve MHC-II+ cells. Activated cells upregulate the gut-homing integrin α4β7 and migrate through the blood circulation to the intestinal lamina propria (LP). After pathogen clearance, L. monocytogenes-elicited γδ T cells become resident memory cells and persist long term in both tissues. Memory γδ T cells undergo a rapid and dramatic re-expansion upon re-exposure to L. monocytogenes and cooperate with conventional T cells to confer heightened protection against the bacterium.
Figure 4
Figure 4
The multifaceted role of resident memory-like γδ T cells in tumorigenesis. Depicted are Vδ2 γδ T cells establishing tissue residency upon being primed by various means (e.g., CMV, bacterial infection, and tumor associated antigens) through localization from the draining lymph nodes to the tissue's epithelial layer. Vδ2+ T cells also localize to the tissue but do not establish permanent residence. Both Vδ2+ and Vδ2 γδ T cell subsets can be polarized from IFNγ anti-tumor subsets toward pro-tumor IL-17A-producing subsets through inflammatory dendritic cell cytokine signaling (e.g., IL-23). One possibility is that pro-inflammatory tissue damage causes a leaky barrier to commensals and other bacteria and a positive feedback loop of inflammation resulting in expansion of IL-17A-producing γδ T cell subsets. Chronic inflammatory exacerbation opens the window for cancer upon mutagenesis due to constant tissue regeneration. IL-17A signaling also causes myeloid-derived suppressor cells (MDSC) to have an immunosuppressive effect on effector T cells. On the other hand, IFNγ-producing tissue resident Vδ2 subsets clonally expand upon recognition of antigen (in part through stress recognition but it has yet to be thoroughly elucidated) causing tumor cell death.

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