Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Abstract

African trypanosomes are single-cell, extra-cellular blood parasites causing profound immunosuppression. Susceptible BALB/c mice infected s.c. into a footpad with 104 Trypanosoma congolense die with fulminating parasitemia within 10 days. We injected BALB/c mice 2 days before such an infection with different doses of a depleting mAb specific for CD25, a surface marker of regulatory T cells (Tregs). Pretreatment with a low, optimal dose of anti-CD25 resulted in a dramatic effect, in that the infected mice did not develop parasitemia, as well as eliminated all parasites and showed no signs of disease. Their spleens showed a 100% reduction of CD4+CD25high T cells and overall a 70% reduction of CD4+CD25+Foxp3+ T cells 7 days postinfection. The protective effect of treatment with an optimal dose of anti-CD25 could be reversed by administration of l-N6-(1-imminoethyl) lysine, a specific inhibitor of inducible NO synthase or administration of anti-CD8 Ab. Analysis of the cytokine patterns and cell surface marker in infected mice pretreated with anti-CD25 Abs pointed to a potential NKT cell response. We then conducted infections in CD1d−/− mice. From our observations, we conclude that CD4+CD25highFoxp3+ Tregs prevent, in normal infected susceptible mice, an early protective response mediated by CD8+ NKT cell-dependent activation of macrophages to kill parasites by production of NO. Our results also indicate that different populations of NKT cells have protective or suppressive effects. Our observations lead us to propose a hypothesis of cross-regulation of NKT cells and Tregs in trypanosome infections.

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

“…Several studies investigated the role of Treg in infections with helminths or other parasites and yielded in diverging conclusions (reviewed in [1] and [13]). There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].…”

Low-Dose Intradermal Infection with Trypanosoma congolense Leads to Expansion of Regulatory T Cells and Enhanced Susceptibility to Reinfection

“…Because we and others have previously shown that regulatory T cells (Tregs) prevent the control of infection with T. congolense (24,25), we wondered whether lowdose intradermal infection was associated with expansion of these cells. Therefore, we infected mice intradermally with 10 3 T. congolense parasites and on the indicated days assessed the percentages and absolute numbers of CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells in the spleens and draining lymph nodes by flow cytometry.…”

“…5A and B). Because previous studies showed that Tregs negatively influence the outcome of T. congolense infection in mice (24,25), we hypothesized that depletion of Tregs during challenge infection will abrogate the enhanced susceptibility mediated by repeated low-dose intradermal infection. We therefore injected mice repeatedly with 10 2 T. congolense parasites (2 times with a 1-week interval), and on the third week injected them with anti-CD25 monoclonal antibody (PC61) to deplete Tregs as we have done previously (25,30).…”

“…Although their primary role is to prevent autoimmunity and suppress inflammatory responses, Tregs have also been implicated in the pathogenesis of several infectious diseases, including those caused by parasites (22)(23)(24). In particular, increased numbers of CD4 ϩ CD25 ϩ Foxp3 ϩ Tregs have been reported in experimental T. congolense infections (25,26), and these cells have been implicated in enhanced susceptibility to the infection (24,25), although the exact mechanisms remain unknown.…”

“…CD4 ϩ T cells that constitutively express CD25 and the transcription factor Foxp3 (called regulatory T cells [Tregs]) have been shown to play a major role in immune homeostasis by actively suppressing several pathological and physiological immune responses in the host (19)(20)(21). Although their primary role is to prevent autoimmunity and suppress inflammatory responses, Tregs have also been implicated in the pathogenesis of several infectious diseases, including those caused by parasites (22)(23)(24). In particular, increased numbers of CD4 ϩ CD25 ϩ Foxp3 ϩ Tregs have been reported in experimental T. congolense infections (25,26), and these cells have been implicated in enhanced susceptibility to the infection (24,25), although the exact mechanisms remain unknown.…”