The expanding impact of T-regs in the skin

Abstract

As the interface between the body and the environment, the skin functions as the physical barrier against external pathogens and toxic agents. In addition, the skin is an immunologically active organ with a plethora of resident adaptive and innate immune cells, as well as effector molecules that provide another layer of protection in the form of an immune barrier. A major subpopulation of these immune cells are the Foxp3 expressing CD4 T cells or regulatory T cells (T-regs). The canonical function of T-regs is to keep other immune cells in check during homeostasis or to dissipate a robust inflammatory response following pathogen clearance or wound healing. Interestingly, recent data has uncovered unconventional roles that vary between different tissues and we will highlight the emerging non-lymphoid functions of cutaneous T-regs. In light of the novel functions of other immune cells that are routinely being discovered in the skin, their regulation by T-regs implies that T-regs have executive control over a broad swath of biological activities in both homeostasis and disease. The blossoming list of non-inflammatory functions, whether direct or indirect, suggests that the role of T-regs in a regenerative organ such as the skin will be a field ripe for discovery for decades to come.

Keywords: adaptive immunity; inflammation; innate immunity; regulatory T (Treg) cells; skin; skin disease; skin immunology.

Figure 1

Different compartments of the skin cycle under homeostatic conditions (Arbitrary levels). The hair follicle is well known to undergo regenerative cycles of anagen (growth), catagen (regression) and telogen (resting phase). Immune cells and dermal white adipose tissue (dWAT) cycle synchronously with respect to different stages of hair follicle. Most of the immune cells follow a similar trend where they increase in number during anagen and decline with catagen and telogen. Interestingly, T-regs cycle in the opposite fashion – T-regs are more in number in the telogen phase than anagen or catagen. This could signify a possible regulatory relationship between these different cell types though mechanisms governing this cyclical behavior are yet to be defined. (–16).

Figure 2

T-regs are at the center of many processes in the skin. (A) T-regs play a direct role in hair follicle cycling by promoting transition from telogen to anagen stage. Loss of T-regs also results in a decrease in dWAT thickness. (B) T-regs establish immune tolerance and prevent microbiome specific inflammation. T-regs also promote wound healing by suppressing IL17-CXCL5-neutophil axis to promote hair follicle stem cell (HFSC) migration. T-regs prevent excessive inflammation (IFNγ and M1 macrophages) to prevent delayed wound healing.

Figure 3

Overview of T-regs in human skin pathologies. A hub and spoke diagram summarizing the potential impact of T-regs and cytokines influencing the niche disease state.