Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post-kala-azar dermal leishmaniasis.
Indian post-kala-azar dermal leishmaniasis (PKDL) is a low-frequency (5-10%) dermal sequela of visceral leishmaniasis (VL) caused by Leishmania donovani; importantly, affected individuals are speculated to be parasite reservoirs. Insight into its immunopathogenesis could translate into rational immunomodulatory therapeutic approaches against leishmaniases. In patients with PKDL (n=21), peripheral lymphocytes were analyzed for surface markers, intracellular cytokines, and lymphoproliferative responses using flow cytometry. In lesional tissue biopsies (n=12), expression of counter-regulatory cytokines (IFN-gamma and IL-10) and the T-regulatory transcription factor forkhead box protein 3 (Foxp3) was analyzed using reverse transcriptase-PCR, along with immunohistochemical detection (n=8) of CD3 and Foxp3 positivity. In patients with PKDL, circulating CD8(+)CD28(-) and antigen-induced IL-10(+)CD3(+) lymphocytes were increased and receded with treatment. CD8(+) lymphocytes showed impaired proliferative responses to L. donovani antigen (LDA) and phytohemagglutinin, which were reinstated after treatment. At presentation, the upregulated lesional IFN-gamma and IL-10 messenger RNA (mRNA), Foxp3 mRNA, and protein were curtailed after treatment. In Indian patients with PKDL, increased frequency of the CD8(+)CD28(-) phenotype, enhanced antigen-specific IL-10 production, and accompanying anergy of circulating lymphocytes suggest their regulatory nature. Furthermore, the concomitantly elevated lesional expression of Foxp3 suggests their possible recruitment into the lesional site, which would sustain disease pathology.
Ganguly
Sudipto
S
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
Mukhopadhyay
Debanjan
D
Das
Nilay K
NK
Chaduvula
Mehervani
M
Sadhu
Soumi
S
Chatterjee
Uttara
U
Rahman
Mehebubar
M
Goswami
Rama P
RP
Guha
Subhashish Kamal
SK
Modak
Dolanchampa
D
Mallik
Sudeshna
S
Gonju
Debananda
D
Pramanik
Netai
N
Barbhuiya
Joyashree N
JN
Saha
Bibhuti
B
Chatterjee
Mitali
M
D000328:Adult; D000953:Antigens, Protozoan / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000469:parasitology / Q000502:physiology; D020405:Dermis / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007194:India; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007893:Leishmania donovani / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000469:parasitology* / Q000502:physiology*
D000953:Antigens, Protozoan; D018106:CD28 Antigens; D017252:CD3 Complex; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016753:Interleukin-10; D007371:Interferon-gamma