Requirements for the development of IL‐4‐producing T cells during intestinal nematode infections: what it takes to make a Th2 cell in vivo

Abstract

Components of the type 2 immune response may mediate host protection against both helminthic parasites and harmful allergic responses. A central player in this response is the T-helper 2 (Th2) effector cell, which produces interleukin (IL)-4, IL-5, IL-13, and other Th2 cytokines during the primary and memory response. Specific aspects of the parasite that trigger Th2-cell differentiation are not yet defined. Furthermore, the cell types and cell surface and secreted molecules that provide the immune milieu required for the development of Th2 effector cells and also Th2 memory cells are not well understood. They will probably vary with the particular helminth or other antigen inducing the Th2 response. We have used third stage larvae of intestinal nematode parasites as adjuvants to promote naïve nonparasite antigen-specific T cells to differentiate into Th2 cells. This model system avoids possible parasite antigen-specific T-cell clones or cross-reactive memory T cells that may preferentially differentiate into Th2 effector cells during the course of infection and confound the stereotypical components of parasite-induced Th2 cell differentiation. We have found that these parasites have a potent adjuvant effect and have used our model system to begin to investigate the events that lead to the development of polarized Th2 cells in vivo.

Protective immune mechanisms in helminth infection

“…Alternatively activated macrophages, which are present in larger numbers than neutrophils, enclose the parasite and neutrophils forming a granulomatous structure. At the border of the granuloma there is an accumulation of CD4 + T cells, CD11c + dendritic cells (DCs) and eosinophils; however, basophils, mast cells, CD8 + T cells, γδT cells and B cells are absent 18,19,21 . Cytokine gene-expression analysis using laser capture microdissection has shown the development of a highly polarized T H 2-type response (high expression levels of IL-4 and IL-13, in the absence of IFNγexpression).…”

Alternatively activated macrophages in helminth infections

“…Helminth infections vary greatly in terms of the interplay between Th1-type and Th2-type inflammatory responses. At one extreme, the enteric immune response to either H. polygyrus or N. brasiliensis, once established, appears to be primarily Th2-type polarized, with little evidence of an underlying Th1-type response [30]. At the other extreme are responses to the intestinal nematode T. muris or the trematode S. mansoni, where a strong underlying Th1-type response can develop if the dominant Th2-type response is inhibited by IL-4R [31] or B7 [32,33] blockade.…”

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

“…These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9].…”

“…The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1][2][3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.…”

“…These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2].…”