Evidence for the opposing roles of different γδ T cell subsets in macrophage homeostasis

Abstract

To ensure invading pathogens are eliminated with minimal damage to host tissues it is essential that macrophage activation be tightly regulated. Previously we demonstrated that a subset of gammadelta T cells (Vgamma1(+)) contributes to resolving pathogen-induced immune responses by killing activated macrophages. However, the exaggerated macrophage response seen in infected Vgamma1(+) T cell-deficient mice suggests that gammadelta T cells play a broader role in macrophage homeostasis and other subsets might promote macrophage activation. Using a macrophage:gammadelta T cell co-culture system we have shown that gammadelta T cells increase the activity of macrophages activated in vivo by Listeria monocytogenes infection. In a dose-dependent manner, gammadelta T cells up-regulated production of cytokines (TNF-alpha, IL-6, IL-10) and chemokines (MIP-1alpha, MIP-1beta) by Listeria-elicited macrophages. The ability to increase macrophage cytokine production was prominent among Vgamma4(+) gammadelta T cells. Reciprocally, Vgamma4(+) gammadelta T cells were activated by Listeria-elicited macrophages, resulting in production of the anti-inflammatory cytokine, IL-10. gammadelta T cell adoptive transfer experiments showed that Vgamma4(+) T cells protected TCRdelta(-/-) mice against Listeria-induced liver injury and necrosis. These findings identify distinct and non-overlapping roles for gammadelta T cell subsets in regulating macrophage function during pathogen-induced immune responses

Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

“…␥␦ T cells engage in regulatory interactions with macrophages and dendritic cells (26) and play a significant role in macrophage homeostasis. Up-regulation of macrophage cytokine production by ␥␦ T cells during bacterial infection was recently demonstrated (27). In ER␤ Ϫ/Ϫ mice, the increased recruitment of macrophages to lamina propria may be caused by activated ␥␦ T cells.…”

Depletion of γδ T Cells Exacerbates Murine Adriamycin Nephropathy

“…TGF-␤ is known to function in a variety of ways to exert an immunoregulatory function (40). TGF-␤ on ␥␦ T cells may act to suppress inflammation directly, potentially through expansion of regulatory T cells or by suppression of macrophages, as shown by Tramonti and others (16,17,41). Although no effect was found in knockout mice that were deficient in ␥␦ T cells by Rosenkranz et al (15), this may be due to either differences in the model or the underlying defects in ␣␤ T cell development that occurs in these mice (42).…”

“…However, in either ␥␦ or ␣␤ knockout, limited macrophage infiltration was seen and ␥␦ T cells seemed to have a permissive role for the development of disease. The importance of ␥␦ T cells in macrophage activation was recently shown as well as potentially differing roles of ␥␦ subsets in macrophage activation and suppression in vitro (16,17). AN is a model of chronic proteinuric renal disease.…”

A subset of IL‐10‐producing γδ T cells protect the liver from Listeria‐elicited, CD8+ T cell‐mediated injury

“…The Listeriainduced liver necrosis that occurs in the absence of cd T cells is prevented by reconstitution with both hepatic and splenic cd T cells expressing a TCR encoded in part by the Vc4 gene segment [38]. Vc1 + T cells, however, play no role in protecting the liver from immune-mediated liver injury since Vc1 -/-mice do not develop liver pathology in response to Listeria infection [32].…”

“…The ability of Vc4 + T cells to protect against Listeria-elicited CD8 + T cell-mediated liver injury was dependent upon their ability to produce IL-10, since reconstitution of TCRd -/-mice with Vc4 + T cells from IL-10-deficient animals failed to prevent liver necrosis and injury after subsequent Listeria infection (Table 2). Since we have shown that the cytokine response of Vc4 T cells to Listeria infection is dominated by IL-10 production, which they produce in response to activated splenic macrophages [38], we determined whether IL-10 production by hepatic Vc4 T cells could be influenced by their interaction with CD8 + T cells. When cultured alone, IL-10 production by hepatic Vc4 T cells was restricted to a small number (<10%) of cells (Fig.…”