Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response.
Lymphatic filariasis leads to profound impairment of parasite-specific T helper type 1 (Th1) and Th2 immune responses and significantly increases the expression of regulatory networks and regulatory effectors like transforming growth factor-β, CD25, cytotoxic T-lymphocyte antigen 4, glucocorticoid-induced tumour necrosis factor receptor (GITR) and regulatory T (Treg) cells, which together play an important role in immunosuppression. While Treg cells suppress the activity of effector cells, monocyte dysfunction, characterized by an alternatively activated immunoregulatory phenotype, is one hypothesis that explains the lack of an antigen-specific T-cell response in infected individuals. In the present study, we administered neutralizing antibodies against the Treg cell-associated markers CD25 and GITR and observed its effects on filaria-induced immunosuppression. Our results show that administration of anti-CD25 and anti-GITR in infected animals not only arrested the accumulation of Treg cells and reduced arginase activity, but also led to an increase in the percentages of Th17 cells in the secondary lymphoid organs of mice. Elevated levels of interferon-γ and decreased levels of interleukin-10 were also noted in the culture supernatants of mouse splenocytes that were treated with neutralizing antibodies. Furthermore, treatment with neutralizing antibodies enhanced the expression of inducible nitric oxide synthase on host macrophages and CD40 on host dendritic cells with concomitant decreased expression of alternative activation markers Arg1, Ym1 and Fizz1, which together lead to reduced parasite burden in treated animals. In summary, administration of neutralizing antibodies helps in breaking the regulatory network in mice and limits parasite-induced immunosuppression at the earliest host-parasite interface.
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.
Manisha
M
Pathak
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.
Pankaj
P
Sharma
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Aditi
A
Sharma
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Meenakshi
M
Verma
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Mrigank
M
Srivastava
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Shailja
S
Misra-Bhattacharya
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D004195:Disease Models, Animal; D004605:Elephantiasis, Filarial / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006790:Host-Parasite Interactions; D007114:Immunization; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D013997:Time Factors
D057134:Antibodies, Neutralizing; D001425:Bacterial Outer Membrane Proteins; D019013:CD40 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D053645:Interleukin-2 Receptor alpha Subunit; C112171:Wsp protein, Wolbachia; D016753:Interleukin-10; D007371:Interferon-gamma
Wolbachia surface protein; anti-CD25; anti-glucocorticoid-induced tumour necrosis factor receptor; immunosuppression; lymphatic filariasis