The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo

Abstract

Naturally occurring CD4 + CD25 hi Foxp3 + Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4 + Foxp3 -(memory) and CD4 + Foxp3 + (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4 + Foxp3 -T cell populations, skin CD4 + Foxp3 + T cells expressed typical Treg markers (i.e., they were CD25 hi , CD127 lo , CD27 + , and CD39 + ) and did not synthesize IL-2 or IFN-γ after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4 + Foxp3 + T cells in skin could be induced from memory CD4 + T cells, we expanded skin-derived memory CD4 + T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4 + Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4 + T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses. IntroductionNaturally occurring CD4 + CD25 hi Foxp3 + Tregs (nTregs) can prevent reactivity to both self and non-self antigens (1-4). Although early studies suggested that these cells are generated as a distinct population in the thymus, CD4 + CD25 hi Foxp3 + Tregs, which are phenotypically and functionally identical to the thymus-derived population, can also be generated after antigen-induced proliferation of CD4 + T cells in peripheral tissues in mice (5, 6). The rapid division of CD4 + CD25 hi Foxp3 + Tregs that has been shown to occur in vivo in mice (7) and humans (8) may be a mechanism for maintaining nTregs. This has particularly important implications for the lifelong maintenance of human Tregs after thymic involution, since CD4 + CD25 hi Foxp3 + T cells in humans have limited capacity for extensive self-renewal, due to short telomeres, and lack telomerase activity (8). It is important to consider the possible difference in behavior and characteristics of nTregs in mice and humans, especially given the potential for species-specific differences that might lead to side effects during therapy (9).The regulation of immunity and pathology by intervention at the Treg axis has been very successful in animal models, where it has been shown that CD4 + CD25 hi Foxp3 + T cells can be harnessed to prevent autoimmunity (10, 11), inflammatory disease (12),

LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

“…They certainly differ from classical Tr1 because they express high levels of CD25, are Foxp3 + , and exert their suppressive function by direct cell-to-cell contact. In addition, recent data in a human setting seem to stress the functional and numerical relevance of adaptive Treg cells, which are likely constantly produced in the periphery from a differentiation stage that is equipped with suppressor functions (3)(4)(5).…”

“…Moreover, recent experimental evidence demonstrated that in humans, adaptive Treg cells may also emerge from the memory CD4 + CD25 2 CD45RO + T cell pool in the presence of antigenic stimulation. These converted Treg cells, once generated, are highly susceptible to apoptotic death, thus representing a highly dynamic T cell pool that mirrors its responsive counterpart (3)(4)(5).…”

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

“…In humans, blood is readily accessible, and techniques such as skin biopsy and skin blister formation have been developed to sample the skin repertoire (18). However, although LN sampling is routine in animals, to date, techniques have not been developed to do so in humans.…”

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

“…However, a growing body of evidence suggests that Tregs must enter tissues to be effective in regulation of local inflammation (21)(22)(23). The observation that healthy skin contains a resident population of Foxp3 + Tregs supports the concept that the ongoing presence of Tregs in organs, particularly those exposed to the external environment, is important in preventing inappropriate inflammation (24,25). Despite this, we know little about the mechanisms whereby Tregs recruited to peripheral tissues regulate local inflammation.…”