Investigating the Impact of Helminth Products on Immune Responsiveness Using a TCR Transgenic Adoptive Transfer System

Abstract

Helminth infections and their products have a potent immunomodulatory effect on the host immune system and can impair immune responses against unrelated Ags. In vitro studies have suggested that the immunomodulation by helminth extracts may be the result of bystander response bias toward a Th2 phenotype and/or an Ag-specific T lymphocyte proliferative hyporesponsiveness. The aim of this study was to determine the role of these potential mechanisms of immunosuppression in vivo. Therefore, using a sensitive model of CFSE-labeled OVA-specific TCR transgenic T lymphocyte adoptive transfer, we analyzed the effect of Ascaris suum body fluid (ABF) on the kinetics and amplitude of a primary OVA-specific T cell response as well as the Th1/Th2 profile of the response in wild-type and IL-4 knockout (KO) mice. We find that inhibition of delayed-type hypersensitivity by ABF was associated with a Th1/Th2 shift in wild-type animals, but not in IL-4 KO mice. The use of this model has allowed us to demonstrate that although the kinetics of the OVA-specific primary response was not affected by ABF, the expansion of the OVA-specific T lymphocytes was significantly inhibited in both wild-type and IL-4 KO mice. This inhibition was associated with a reduced proliferative capacity of these cells in vivo, distinct from anergy.

Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling

“…This concept is consistent with observations in other Th2 induction systems involving allergic (66,67) as well as helminthtriggered responses (53,68), in which decreased rather than increased CD4 T cell function has been noted. The findings reported in this work now link this behavior to down-regulatory signals in the APC compartment itself, which in turn are associated with retarded lymphocyte activation.…”

Inhibition of Autoimmune Type 1 Diabetes by Gastrointestinal Helminth Infection

“…The immune response to the larval muscle stage of T. spiralis is also characterized by a Th2 response, and this is coupled with an intense IL-10 response which is crucial for controlling the accompanying inflammation (5). These two parasites are therefore present and manipulating the immune response for the duration of the study; it would therefore be of interest to determine if parasite products could elicit similar responses, as has been demonstrated both for diabetes and in other systems (1,4,6,7,9,21,48,50).…”

“…Helminth parasites are strong inducers of T helper 2 (Th2) cell-associated responses such as eosinophilia, interleukin-4 (IL-4), IL-5, IL-13, and immunoglobulin E (IgE) production (20,29). In addition to the Th2 polarizing response, the induction of regulatory responses is also a common feature of the immune response induced following exposure to parasitic helminth antigens (6,30,49).…”

Immunosuppressive components of Ascaris suum down‐regulate expression of costimulatory molecules and function of antigen‐presenting cells via an IL‐10‐mediated mechanism

“…There is irrefutable evidence that helminth infections can down-regulate immune responsiveness to other types of infection or to unrelated Ag [5][6][7][26][27][28][29]. We have previously shown that Asc or PI have the same ability as a live infection to strongly suppress the immune response and to induce a typical Th2 response (with IL-4 and IL-10 secretion) which is responsible for the suppressive effect [10][11][12][13][14].…”

“…However, some helminths are able to persist in their hosts for many years, creating an anti-inflammatory environment favorable to their survival and maintenance. In this context, it has been demonstrated that helminths down-regulate host's immunity to their own Ag and to a large number of unrelated pathogenic agents [5][6][7]. More recently, it has been reported that some helminth infections promote the generation of T regulatory cells which are responsible in part for the state of immune hyporesponsiveness [8][9][10].…”