BMC Infectious Diseases | |
Role of CD8+ T cells in protection against Leishmania donovani infection in healed Visceral Leishmaniasis individuals | |
Poonam Salotra1  Gérard Papierok2  Jean-Loup Lemesre3  Narender Singh Negi4  Rachel Bras-Gonçalves3  Himanshu Kaushal1  | |
[1] National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi 110029, India;Virbac, Carros, France;Institut de Recherche pour le Développement, UMR177 IRD/CIRAD “INTERTRYP”, Montpellier, France;Department of Medicine, VMMC & Safdarjung Hospital, New Delhi, India | |
关键词: Vaccine; Total soluble Leishmania antigens; Visceral leishmaniasis; Granzyme B; CD8+ T cells; | |
Others : 1118255 DOI : 10.1186/s12879-014-0653-6 |
|
received in 2014-05-15, accepted in 2014-10-29, 发布年份 2014 | |
【 摘 要 】
Background
Majority of individuals with history of visceral leishmaniasis (VL) exhibit strong immunity to re-infection, however, the mechanism of resistance is poorly understood. It is unclear whether CD8+ T cells contribute to protection against Leishmania donovani infection through cytotoxic activity. The present study aims to evaluate immunological mechanism associated with resistance to the disease in healed VL (HVL) individuals and further, the contribution of CD8+ T cells in the protective immunity.
Methods
Peripheral blood mononuclear cells (PBMCs) from VL, HVL and naive groups were exposed in vitro to total soluble Leishmania antigen (TSLA) from L. donovani. The proliferation index was determined by ELISA based lymphoproliferative assay. Cytokines and granzyme B levels were measured by CBA. Activated T-cell populations were estimated using flow cytometry.
Results
We observed significantly higher lymphoproliferation, cytokines and granzyme B levels in HVL group compared to naive or VL group. More strikingly, we found a strong association (rs = 0.895, P < 0.0001) between proliferation index (PI) and granzyme B level, with a significant proportion of activated CD8+ T cells in HVL group.
Conclusions
Leishmania immune group (HVL) exhibited durable and strong cellular immune response to TSLA in terms of lymphoproliferation as well as production of Th1 cytokines and granzyme B. Additionally, the elevated level of activated CD8+ T cells and stimulation of cytotoxic activity through granzyme B production, indicated a possible role of CD8+ T cells in resistance to L. donovani infection in the HVL group.
【 授权许可】
2014 Kaushal et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150206022059595.pdf | 810KB | download | |
Figure 4. | 61KB | Image | download |
Figure 3. | 12KB | Image | download |
Figure 2. | 31KB | Image | download |
Figure 1. | 11KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
【 参考文献 】
- [1]Control of the Leishmaniases World Health Organ Tech Rep Ser 2010, 949:91-106.
- [2]Alvar J, Yactayo S, Bern C: Leishmaniasis and poverty. Trends Parasitol 2006, 22:52-57.
- [3]Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, WHO Leishmaniasis Control Team: Leishmaniasis worldwide and global estimates of its incidence.PLoS One 2012, 7:e35671.
- [4]Ramesh V, Singh R, Salotra P: Post-kala-azar dermal leishmaniasis – an appraisal. Trop Med Int Health 2007, 12:848-851.
- [5]Manson-Bahr PE: Immunity in kala-azar. Trans R Soc Trop Med Hyg 1961, 55:550-555.
- [6]Haldar JP, Ghose S, Saha KC, Ghose AC: Cell-mediated immune response in Indian kala-azar and post-kala-azar dermal leishmaniasis. Infect Immun 1983, 42:702-707.
- [7]Hailu A, Menon JN, Berhe N, Gedamu L, Hassard TH, Kager PA, Olobo J, Bretscher PA: Distinct immunity in patients with visceral leishmaniasis from that in subclinically infected and drug-cured people: implications for the mechanism underlying drug cure. J Infect Dis 2001, 184:112-115.
- [8]Kubar J, Fragaki K: Recombinant DNA-derived Leishmania proteins: from the laboratory to the field. Lancet Infect Dis 2005, 5:107-114.
- [9]Saha S, Mondal S, Banerjee A, Ghose J, Bhowmick S, Ali N: Immune responses in kala-azar. Indian J Med Res 2006, 123:245-266.
- [10]Clarêncio J, de Oliveira CI, Favali C, Medina O, Caldas A, Costa CH, Costa DL, Brodskyn C, Barral A, Barral-Netto M: Could the lower frequency of CD8+CD18+CD45RO+ lymphocytes be biomarkers of human VL? Int Immunol 2009, 21:137-144.
- [11]Gautam S, Kumar R, Singh N, Singh AK, Rai M, Sacks D, Sundar S, Nylén S: CD8 T cell exhaustion in human visceral leishmaniasis. J Infect Dis 2014, 209:290-299.
- [12]Stern JJ, Oca MJ, Rubin BY, Anderson SL, Murray HW: Role of L3T4+ and LyT-2+ cells in experimental visceral leishmaniasis. J Immunol 1988, 140:3971-3977.
- [13]Tsagozis P, Karagouni E, Dotsika E: CD8 (+) T cells with parasite-specific cytotoxic activity and a Tc1 profile of cytokine and chemokine secretion develop in experimental visceral leishmaniasis. Parasite Immunol 2003, 25:569-579.
- [14]Joshi T, Rodriguez S, Perovic V, Cockburn IA, Stäger S: B7-H1 Blockade Increases Survival of Dysfunctional CD8+ T Cells and Confers Protection against Leishmania donovani Infections.PLoS Pathog 2009, 5:e1000431.
- [15]Esch KJ, Juelsgaard R, Martinez PA, Jones DE, Petersen CA: Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. J Immunol 2013, 191:5542-5550.
- [16]Mary C, Auriault V, Faugere B, Dessein AJ: Control of Leishmania infantum infection is associated with CD8 (+) and gamma interferon and interleukin-5-producing CD4 (+) antigen-specific T cells. Infect Immun 1999, 67:5559-5566.
- [17]Nateghi Rostami M, Keshavarz H, Edalat R, Sarrafnejad A, Shahrestani T, Mahboudi F, Khamesipour A: CD8+ T cells as a source of IFN-gamma production in human cutaneous leishmaniasis.PLoS Negl Trop Dis 2010, 4:e845.
- [18]Wizel B, Palmieri M, Mendoza C, Arana B, Sidney J, Sette A, Tarleton R: Human infection with Trypanosoma cruzi induces parasite antigen-specific cytotoxic T lymphocyte responses. J Clin Invest 1998, 102:1062-1071.
- [19]Smith SM, Malin AS, Pauline T, Lukey , Atkinson SE, Content J, Huygen K, Dockrell HM: Characterization of human Mycobacterium bovis bacille Calmette-Gue’rin–reactive CD8+ T cells. Infect Immun 1999, 67:5223-5230.
- [20]Cho S, Mehra V, Thoma-Uszynski S, Stenger S, Serbina N, Mazzaccaro RJ, Flynn JL, Barnes PF, Southwood S, Celis E, Bloom BR, Modlin RL, Sette A: Antimicrobial activity of MHC class I–restricted CD8+ T cells in human tuberculosis. Proc Natl Acad Sci U S A 2000, 97:12210-12215.
- [21]Arvå E, Andersson B: Kinetics of cytokine release and expression of lymphocyte cell-surface activation markers after in vitro stimulation of human peripheral blood mononuclear cells with Streptococcus pneumoniae. Scand J Immunol 1999, 49:237-243.
- [22]Goto H, Prianti MD: Immunoactivation and immunopathogeny during active visceral leishmaniasis. Rev Inst Med Trop Sao Paulo 2009, 51:241-246.
- [23]Kushawaha PK, Gupta R, Tripathi CD, Sundar S, Dube A: Evaluation of Leishmania donovani protein disulfide isomerase as a potential immunogenic protein/vaccine candidate against visceral Leishmaniasis.PLoS One 2012, 7:e35670.
- [24]Saha S, Mondal S, Ravindran R, Bhowmick S, Modak D, Mallick S, Rahman M, Kar S, Goswami R, Guha SK, Pramanik N, Saha B, Ali N: IL-10- and TGF-beta-mediated susceptibility in kala-azar and post-kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India. J Immunol 2007, 179:5592-5603.
- [25]Ghosh DJ, Levy DE, Johnstone RW, Clarke CJ: IFNγ signaling- does it mean JAK-STAT? Cytokine Growth Factor Rev 2008, 19:282-394.
- [26]Mosser DM, Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008, 8:958-969.
- [27]Sacks D, Noben-Trauth N: The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2002, 2:845-858.
- [28]Peruhype-Magalhães V, Martins-Filho OA, Prata A, de Silva L, Rabello A, Teixeira-Carvalho A, Figueiredo RM, Guimarães-Carvalho SF, Ferrari TC, Van Weyenbergh J, Correa-Oliveira R: Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-gamma and interleukin-10 and low frequency of tumour necrosis factor-alpha (+) monocytes are hallmarks of active human visceral Leishmaniasis due to Leishmania chagasi infection. Clin Exp Immunol 2006, 46:124-132.
- [29]Ghalib HW, Whittle JA, Kubin M, Hashim FA, el-Hassan AM, Grabstein KH, Trinchieri G, Reed SG: IL-12 enhances Th1-type responses in human Leishmania donovani infections. J Immunol 1995, 154:4623-4629.
- [30]Carvalho EM, Badaró R, Reed SG, Jones TC, Johnson WD Jr: Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Inves 1985, 76:2066-2069.
- [31]Chamakh-Ayari R, Bras-Gonçalves R, Bahi-Jaber N, Petitdidier E, Markikou-Ouni W, Aoun K, Moreno J, Carrillo E, Salotra P, Kaushal H, Negi NS, Arevalo J, Falconi-Agapito F, Privat A, Cruz M, Pagniez J, Papierok GM, Rhouma FB, Torres P, Lemesre JL, Chenik M, Meddeb-Garnaoui A: In vitro evaluation of a soluble Leishmania promastigote surface antigen as a potential vaccine candidate against human leishmaniasis.PLoS One 2014, 9:e92708.
- [32]Vouldoukis I, Bécherel PA, Riveros-Moreno V, Arock M, da Silva O, Debré P, Mazier D, Mossalayi MD: Interleukin-10 and interleukin-4 inhibit intracellular killing of Leishmania infantum and Leishmania major by human macrophages by decreasing nitric oxide generation. Eur J Immun 1997, 27:860-865.
- [33]Bousoffara T, Louzir H, Ben Salah A, Dellagi K: Analysis of granzyme B activity as a surrogate marker of Leishmania-specific cell-mediated cytotoxicity in zoonotic cutaneous leishmaniasis. J Infect Dis 2004, 189:1265-1273.
- [34]Kägi D, Vignaux F, Ledermann B, Bürki K, Depraetere V, Nagata S, Hengartner H, Golstein P: Fas and perforin pathways as major mechanisms of T-cell–mediated cytotoxicity. Science 1994, 265:528-530.
- [35]Lowin B, Hahne M, Mattmann C, Tschopp J: Cytotoxic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994, 370:650-652.
- [36]Barral-Netto M, Barral A, Brodskyn C, Carvalho EM, Reed SG: Cytotoxicity in human mucosal and cutaneous leishmaniasis. Parasite Immunol 1995, 17:21-28.
- [37]Brodskyn CI, Barral A, Boaventura V, Carvalho E, Barrel-Netto M: Parasite-driven in vitro human lymphocyte cytotoxicity against autologous infected macrophages from mucosal leishmaniasis. J Immunol 1997, 159:4467-4473.
- [38]Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ: Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 1994, 76:977-987.
- [39]McElhaney JE, Pinkoski MJ, Upshaw CM, Bleackley RC: The cell mediated cytotoxic response to influenza vaccination using an assay for granzyme B activity. J Immunol Methods 1996, 190:11-20.
- [40]Griffiths GM, Muller C: Expression of perforin and granzymes in vivo: potential diagnostic markers for activated cytotoxic cells. Immunol Today 1991, 12:415-419.
- [41]Sharp M, Terada K, Wilson A, Nader S, Kinchington PE, Ruyechan WT, Hay J, Arvin AM: Kinetics and viral protein specificity of cytotoxic T lymphocyte response in healthy adults immunized with live attenuated varicella vaccine. J Infect Dis 1992, 165:852-858.