Chronic Helminth Infection Induces Alternatively Activated Macrophages Expressing High Levels of CCR5 with Low Interleukin-12 Production and Th2-Biasing Ability

Abstract

Helminth infections induce Th2-type biased immune responses. Although the mechanisms involved in this phenomenonare not yet clearly defined, antigen-presenting cells (APC) could play an important role in this process. Here, we have used peritoneal macrophages (F4/80؉) recruited at different times after challenge with Taenia crassiceps as APC and tested their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of interleukin-12 (IL-12) and nitric oxide (NO), paralleled with low levels of IL-6 and prostaglandin E 2 (PGE 2 ) and with the ability to induce strong antigen-specific CD4؉ T-cell proliferation in response to nonrelated antigens. In contrast, macrophages from chronic infections produced higher levels of IL-6 and PGE 2 and had suppressed production of IL-12 and NO, associated with a poor ability to induce antigen-specific proliferation in CD4 ؉ T cells. Failure to induce proliferation was not due to a deficient expression of accessory molecules, since major histocompatibility complex class II, CD40, and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed. These macrophages from chronic infections were able to bias CD4 ؉ T cells to produce IL-4 but not gamma interferon (IFN-␥), contrary to macrophages from acute infections. Blockade of B7-2 and IL-6 and inhibition of PGE 2 failed to restore the proliferative response in CD4 ؉ T cells. Furthermore, studies using STAT6 ؊/؊ mice revealed that STAT6-mediated signaling was essential for the expansion of these alternatively activated macrophages. These data demonstrate that helminth infections can induce different macrophage populations that have Th2-biasing properties.

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

“…These have been shown to suppress proliferation of Ag-specific T cells through a contact-dependent mechanism (58). However, alternatively activated macrophages do not develop in filarial-infected IL-4R Ϫ/Ϫ mice (J. E. Allen, unpublished observation), or in STAT6-deficient animals infected with other helminths (59,60). By showing that B. malayi induces Foxp3 within the T cell population even in the absence of IL-4R signaling, we have established that this process is independent of alternatively activated macrophages.…”

Alternatively activated macrophages in helminth infections

“…AAMΦs are observed in a variety of helminth infections, including Th2-type immune responses to Schistosoma mansoni [2], Heligmosomoides polygyrus [3], Nippostrongylus brasiliensis [4], Taenia crassiceps [5], Trichinella spiralis [6], Fasciola hepatica [7], Ascaris suum [8], and filarial parasites [9]. A number of markers are used to identify AAMΦs ( Figure 1).…”

Pathological Role of Large Intestinal IL-12p40 for the Induction of Th2-Type Allergic Diarrhea

“…9 It has been suggested that antigen-presenting cells (APCs) play a crucial role in the skewing of Th1 and Th2 differentiation. 10,11 IL-12 is a heterodimeric cytokine composed of p40 and p35 which strongly promotes the differentiation of naive CD4 ϩ T cells to the Th1 phenotype and suppresses the synthesis of Th2-type cytokines. 12 IL-12 is produced primarily by APCs and the production is regulated by IL-10 and IFN-␥.…”