Immunopathology in schistosomiasis is controlled by antigen‐specific regulatory T cells primed in the presence of TLR2

Abstract

Regulatory T cells (Treg) are vital in maintaining the homeostasis of immune reactions. In chronic infections, such as schistosomiasis, it remains unclear whether engagement of the TLR family is required to induce Treg activity. Thus, we performed in vivo studies using TLR2 -/-mice infected with Schistosoma mansoni and found elevated immunopathology, decreased egg burden and extended antigen-specific Th1 responses. Simultaneously, the population of Treg failed to expand. To evaluate the role of Treg during infection, we functionally inactivated CD4 + CD25 + T cells and observed that the resulting immunopathology mirrored that in TLR2 -/-mice. Egg burden was also reduced in anti-CD25-treated mice, indicating that without Treg eggs are more efficiently destroyed. In addition, antigen-specific T cells from both TLR2 -/-and anti-CD25-treated mice displayed an extended Th1 phase. Finally, adoptive transfer of schistosome-primed, but not naive CD4 + CD25 + T cells was able to resolve the immunopathology in TLR2 -/-recipients and interestingly, this amelioration was independent of TLR2 being present on the transferred Treg. We conclude that TLR2 is necessary for priming active Treg and their expansion during schistosomiasis.

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

“…TLR have previously been shown to be involved in S. mansoni antigen recognition by DC [12,[14][15][16][17], and for this reason, we analyzed TLR expression in CD4 1 T cells from NOD and C57BL/6 mice. We found that both the mRNA and surface protein levels of TLR1 and TLR6 are significantly higher in NOD mouse CD4 1 T cells ( Fig.…”

“…1). Taking into considera- tion the involvement of TLR2 [12,[14][15][16][17] in S. mansoniinduced immunomodulation, the disparate response by NOD and C57BL/6 CD4 1 T cells to TLR2 ligation may provide a partial explanation for the differential response to SEA in the two strains.…”

“…In this study, we highlighted the importance of CLR and TLR in the T-cell response we observed to SEA. Schistosome-derived products have been shown to bind both CLR and TLR on APC with roles identified for both TLR2 and DC-SIGN in the human and TLR2 in mice [14][15][16][17]26]. In this study, we provided evidence that in addition to its effects on DC, SEA also mediated effects directly on CD4 1 T cells, inducing surface-bound LAP and expression of the CLR DEC-205 and galectin-3 on T cells from NOD but not C57BL/6 mice ( Fig.…”

“…The modulation of TLR signaling by S. mansoni antigen has been most widely studied on DC and MF [9][10][11][12][13]. TLR2 has been shown to recognize molecules within SEA [14,15], and it has been suggested that it may participate in the control of immunopathology during S. mansoni infection, in part through effects on the priming and expansion of Treg [16]. However, another report found that TLR2 appears to be dispensable in the control of pathology and infection [17], and TLR2 has been shown not to be required to modulate the activation of DC or their ability to induce a Th2 response [18,19].…”

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

“…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].In a previous study we observed quantitative and qualitative changes in Treg subsets in mice infected with Heligmosomoides polygyrus bakeri. Treg derived from infected mice displayed an activated phenotype, parasite-specificity and an extraordinary strong suppressive activity on conventional T cells [21].…”