Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1

Abstract

Activated T lymphocytes differentiate into effector cells tailored to meet disparate challenges to host integrity. For example, type 1 and type 2 helper (T(H)1 and T(H)2) cells secrete cytokines that enhance cell-mediated and humoral immunity, respectively. The chemokine monocyte chemoattractant protein-1 (MCP-1) can stimulate interleukin-4 production and its overexpression is associated with defects in cell-mediated immunity, indicating that it might be involved in T(H)2 polarization. Here we show that MCP-1-deficient mice are unable to mount T(H)2 responses. Lymph node cells from immunized MCP-1(-/-) mice synthesize extremely low levels of interleukin-4, interleukin-5 and interleukin-10, but normal amounts of interferon-gamma and interleukin-2. Consequently, these mice do not accomplish the immunoglobulin subclass switch that is characteristic of T(H)2 responses and are resistant to Leishmania major. These effects are direct rather than due to abnormal cell migration, because the trafficking of naive T cells is undisturbed in MCP-1(-/-) mice despite the presence of MCP-1-expressing cells in secondary lymphoid organs of wild-type mice. Thus, MCP-1 influences both innate immunity, through effects on monocytes, and adaptive immunity, through control of T helper cell polarization.

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…Nonetheless, the preferential reduction of the levels of anti-AChR IgG2b suggested altered Th cell function. CCL2 plays a role in the development of both Th2 and Th1 cells [11,23]. In our model, IFN-c production by CD4 + T and CD8 + T cells in response to AChR stimulation was marginally impaired in CCL2 -/-mice ( Fig.…”

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

“…In contrast to IL-10 production in response to septic peritonitis in vivo or Toll-like receptor engagement in vitro, lymph node cells from CCL2-deficient mice immunized with ovalbumin were impaired in their capacity to produce IL-10 following in vitro restimulation with antigen [42]. It should be considered, however, that under these experimental conditions IL-10 was produced by T lymphocytes, whereas in LPS-treated mice and mice subjected to septic peritonits IL-10 is predominantly released by macrophages.…”

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses

“…Studies in CCL2/ MCP-1 -/-mice have indicated that this chemokine may be important for the induction and expression of polarized type 2 responses. Interestingly, data in CCR2 -/-mice have pointed to the opposite direction as far as polarized responses are concerned (33,62). In contrast, consistent results between gene targeting of the agonist and of the receptor have been obtained in terms, for instance, of susceptibility to atherosclerosis.…”

“…Some chemokines, including CCL2/MCP-1, induce IL-10 in macrophages. Moreover, data in knockout mice suggest that CCL2/ MCP-1 polarizes immunity in a type 2 direction (62). Chronic exposure to high chemokine concentrations in the tumor microenvironment may set in motion a chemokinecentered vicious circuit, leading to skewing towards a type 2 inflammatory response (77).…”