F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Abstract

Both T cells and APC have been strongly implicated in the immune suppression observed during filarial nematode infections, but their relative roles are poorly understood, particularly in regard to timing and locality of action. Using Litomosoides sigmodontis infection of susceptible BALB/c mice, we have studied the progression of filarial immunosuppression leading to patent infection with blood microfilaremia. Patent infection is associated with decreased immune responsiveness in the draining thoracic lymph nodes (tLN) and intrinsically hyporesponsive CD4+ T cells at the infection site. We now show that we are able to separate, both in time and space, different suppressive mechanisms and cell populations that contribute to filarial hyporesponsiveness. L. sigmodontis infection recruited a F4/80+ population of alternatively activated macrophages that potently inhibited Ag-specific CD4+ T cell proliferative responses even in the presence of competent naive APC. T cell responsiveness was partially restored by neutralizing TGF-β, but not by blocking IL-10 or CTLA-4 signaling. During prepatent infection, the macrophage population was restricted to the infection site. However, once infection became patent with systemic release of microfilariae, the suppressive macrophage activity extended peripherally into the tLN. In contrast, the hyporesponsive CD4+ T cell phenotype remained localized at the infection site, and the tLN CD4+ T cell population recovered full Ag responsiveness in the absence of suppressive macrophages. Filarial immunosuppression, therefore, evolves over time at sites increasingly distal to infection, and the mechanisms of filarial down-regulation are dependent on proximity to the infection site.

Alternatively activated macrophages in helminth infections

“…NeMΦs recruited to the peritoneum following implantation of Brugia malayi adult worms express arginase-1, Ym1, and FIZZ1/RELMα [10]. Similarly, recent studies of Litomosoides sigmodontis infection showed recruitment of argininase-1-expressing F4/80 + macrophages [23]. In the strictly enteric H. polygyrus infection, during memory, but not primary, responses, AAMΦs accumulate at sites of larval invasion in the submucosa as early as four days after inoculation.…”

“…In the memory Th2-type response to H. polygyrus, in vivo depletion of macrophages with chlodronate liposomes had no effect on the potent Th2-type cytokine response [3]. Furthermore, following L. sigmodontis infection, although AAMΦs could inhibit T cell proliferation in vitro, little effect on Th2-cell IL-4 and IL-5 was observed [23].…”

“…Infection with L. sigmodontis also induces AAMΦs, which can suppress in vitro T cell proliferation. Further in vitro studies suggest that the mechanism of T cell suppression is independent of IL-10 and CTLA-4, but partially dependent on TGF-β [23]. Costimulatory molecules are important regulators of T cell activation, with B7-1 and B7-2 on APCs interacting with the T cell ligands CD28, to provide positive signals [34], or CTLA-4, to provide negative signals [35].…”

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

“…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. In long-term L. sigmodontis infections, alternatively activated macrophages are found together with both Foxp3 ϩ Tregs and CTLA-4 ϩ anergic effector T cells (39), although the interdependency of these populations has not been established. In our short-term experimental system, CTLA-4 remained high on Foxp3 Ϫ effector cells even in the IL-4R Ϫ/Ϫ setting, whereas CD4 ϩ FoxP3 ϩ cell expression of CD25, CD103, and CTLA-4, were indistinguishable from wild-type (data not shown).…”

Th2 Cytokine-Induced Alterations in Intestinal Smooth Muscle Function Depend on Alternatively Activated Macrophages

“…Alternatively activated macrophages are linked to the suppression of T cell responsiveness in chronic infections 22 and are important for down regulation of Th2 mediated immune pathology. In the present study, macrophage depletion did not change either Th1 (IFN-γ) or Th2 (IL-4, IL-13) cytokine expression, suggesting that macrophages are not involved in the initiation of the cytokine response elicited by N. brasiliensis infection, but are part of the downstream events in response to increased Th2 cytokine production.…”