2016;**6**:1520. DOI: 10.3389/ fmicb.2015.01520

[91] Melby PC, Andrade-Narvaez FJ, Darnell BJ, Valencia-Pacheco G, Tryon VV, Palomo-Cetina A. Increased expression of proinflammatory cytokines in chronic lesions of human cutaneous leishmaniasis. Infection and Immunity. 1994;**62**:837-842. DOI: 10.1128/IAI.62.3.837-842.1994

[92] Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected with *Leishmania major*. The Journal of Experimental Medicine. 1993;**177**:1505-1509. DOI: 10.1084/ jem.177.5.1505

[93] Sypek JP, Chung CL, Mayor SEH, Subramanyam JM, Goldman SJ, Sieburth DS, et al. Resolution of cutaneous leishmaniasis: Interleukin 12 initiates a protective T helper type 1 immune response. The Journal of Experimental Medicine. 1993;**177**: 1797-1802. DOI: 10.1084/jem.177.6.1797

[94] Carneiro MB, Lopes ME, Hohman LS, Romano A, David BA, Kratofil R, et al. Th1-Th2 cross-regulation controls early leishmania infection in the skin by modulating the size of the permissive monocytic host cell reservoir. Cell Host & Microbe. 2020;**27**:752-768.e7. DOI: 10.1016/j.chom.2020.03.011

[95] Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y. Role for CD4+ CD25+ regulatory T cells in reactivation of persistent Leishmaniasis and control of concomitant immunity. The Journal of Experimental Medicine. 2004;**200**:201- 210. DOI: 10.1084/jem.20040298

[96] Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM. Cure of murine leishmaniasis with antiinterleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. The Journal of

Experimental Medicine. 1990;**171**:115- 127. DOI: 10.1084/jem.171.1.115

[97] Kane MM, Mosser DM. The role of IL-10 in promoting disease progression in Leishmaniasis. Journal of Immunology. 2001;**166**:1141-1147. DOI: 10.4049/jimmunol.166.2.1141

[98] Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control *Leishmania major* persistence and immunity. Nature. 2002;**420**:502-507. DOI: 10.1038/nature01152

[99] Nylén S, Sacks D. Interleukin-10 and the pathogenesis of human visceral leishmaniasis. Trends in Immunology. 2007;**28**:378-384. DOI: 10.1016/j. it.2007.07.004

[100] Carneiro MBH, Lopes MEDM, Vaz LG, Sousa LMA, Dos Santos LM, De Souza CC, et al. IFN-γ-dependent recruitment of CD4+ T cells and macrophages contributes to pathogenesis during leishmania amazonensis infection. Journal of Interferon & Cytokine Research. 2015;**35**:935-947. DOI: 10.1089/jir.2015.0043

[101] Novais FO, Scott P. CD8+ T cells in cutaneous leishmaniasis: The good, the bad, and the ugly. Seminars in Immunopathology. 2015;**37**:251-259. DOI: 10.1007/s00281-015-0475-7

[102] Belkaid Y, Von Stebut E, Mendez S, Lira R, Caler E, Bertholet S, et al. CD8 + T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with *Leishmania major*. Journal of Immunology. 2002;**168**:3992-4000. DOI: 10.4049/jimmunol.168.8.3992

[103] Novais FO, Carvalho LP, Graff JW, Beiting DP, Ruthel G, Roos DS, et al. Cytotoxic T cells mediate pathology and metastasis in cutaneous Leishmaniasis. PLoS Pathogens. 2013;**9**:e1003504. DOI: 10.1371/ journal.ppat.1003504

*Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis DOI: http://dx.doi.org/10.5772/intechopen.101160*

[104] Soong L, Chang CH, Sun J, Longley BJ, Ruddle NH, Flavell RA, et al. Role of CD4+ T cells in pathogenesis associated with *Leishmania amazonensis* infection. Journal of Immunology. 1997;158:5374-5383. PMID: 9164958

[105] Uzonna JE, Joyce KL, Scott P. Low dose *Leishmania major* promotes a transient T helper cell type 2 response that is down-regulated by interferon γ–producing CD8+ T cells. The Journal of Experimental Medicine. 2004;**199**:1559- 1566. DOI: 10.1084/jem.20040172

[106] Novais FO, Nguyen BT, Scott P. Granzyme B inhibition by tofacitinib blocks the pathology induced by CD8 T cells in cutaneous Leishmaniasis. The Journal of Investigative Dermatology. 2021;**141**:575-585. DOI: 10.1016/j. jid.2020.07.011

[107] Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS, et al. Antigen requirements for efficient priming of CD8+ T cells by *Leishmania major*-infected dendritic cells. Infection and Immunity. 2005;**73**:6620-6628. DOI: 10.1128/ IAI.73.10.6620-6628.2005

[108] Da-Cruz AM, Oliveira-Neto MP, Bertho ÁL, Mendes-Aguiar CO, Coutinho SG. T cells specific to Leishmania and other nonrelated microbial antigens can migrate to human Leishmaniasis skin lesions. The Journal of Investigative Dermatology. 2010;**130**: 1329-1336. DOI: 10.1038/jid.2009.428

[109] Cardoso TM, Machado Á, Costa DL, Carvalho LP, Queiroz A, Machado P, et al. Protective and pathological functions of CD8 + T Cells in *Leishmania braziliensis* infection. Infection and Immunity. 2015;**83**: 898-906. DOI: 10.1128/IAI.02404-14

[110] Santos CDS, Boaventura V, Ribeiro Cardoso C, Tavares N, Lordelo MJ, Noronha A, et al. CD8+ granzyme B+–mediated tissue injury vs. CD4+IFNγ+−mediated parasite killing

in human cutaneous Leishmaniasis. The Journal of Investigative Dermatology. 2013;**133**:1533-1540. DOI: 10.1038/ jid.2013.4

[111] Novais FO, Carvalho AM, Clark ML, Carvalho LP, Beiting DP, Brodsky IE, et al. CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production. PLoS Pathogens. 2017;**13**:e1006196. DOI: 10.1371/journal. ppat.1006196

[112] Faria DR, Souza PEA, Durães FV, Carvalho EM, Gollob KJ, Machado PR, et al. Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis. Parasite Immunology. 2009;**31**:432-439. DOI: 10.1111/j.1365-3024.2009.01125.x

[113] Yurchenko E, Tritt M, Hay V, Shevach EM, Belkaid Y, Piccirillo CA. CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of *Leishmania major* infection favors pathogen persistence. The Journal of Experimental Medicine. 2006;**203**: 2451-2460. DOI: 10.1084/jem.20060956

[114] Suffia IJ, Reckling SK, Piccirillo CA, Goldszmid RS, Belkaid Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. The Journal of Experimental Medicine. 2006;**203**:777- 788. DOI: 10.1084/jem.20052056

[115] Okwor I, Liu D, Beverley SM, Uzonna JE. Inoculation of killed *Leishmania major* into immune mice rapidly disrupts immunity to a secondary challenge via IL-10-mediated process. Proceedings of the National Academy of Sciences. 2009;**106**:13951- 13956. DOI: 10.1073/pnas.0905184106

[116] Ji J, Masterson J, Sun J, Soong L. CD4 + CD25 + regulatory T cells restrain pathogenic responses during *Leishmania amazonensis* infection. Journal of

Immunology. 2005;**174**:7147-7153. DOI: 10.4049/jimmunol.174.11.7147

[117] Woelbing F, Kostka SL, Moelle K, Belkaid Y, Sunderkoetter C, Verbeek S, et al. Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity. The Journal of Experimental Medicine. 2006;**203**: 177-188. DOI: 10.1084/jem.20052288

[118] Miles SA, Conrad SM, Alves RG, Jeronimo SMB, Mosser DM. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. The Journal of Experimental Medicine. 2005;**201**: 747-754. DOI: 10.1084/jem.20041470

[119] Hurdayal R, Ndlovu HH, Revaz-Breton M, Parihar SP, Nono JK, Govender M, et al. IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases. Proceedings of the National Academy of Sciences of the United States of America. 2017;**114**:E8430-E8439. DOI: 10.1073/ pnas.1708125114

[120] Radwanska M, Cutler AJ, Hoving JC, Magez S, Holscher C, Bohms A, et al. Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to *Leishmania major* infection. PLoS Pathogens. 2007;**3**:e68. DOI: 10.1371/ journal.ppat.0030068

[121] Mandell MA, Beverley SM. Continual renewal and replication of persistent *Leishmania major* Parasites in concomitantly immune hosts. Proceedings of the National Academy of Sciences of the United States of America. 2017;**114**:E801-E810. DOI: 10.1073/ pnas.1619265114

[122] Mendonça MG, de Brito MEF, Rodrigues EHG, Bandeira V, Jardim ML, Abath FGC. Persistence of Leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: Is there a sterile cure? The Journal of

Infectious Diseases. 2004;**189**: 1018-1023. DOI: 10.1086/382135

[123] Okwor I, Uzonna J. Persistent parasites and immunologic memory in cutaneous leishmaniasis: Implications for vaccine designs and vaccination strategies. Immunologic Research. 2008;**41**:123-136. DOI: 10.1007/ s12026-008-8016-2

[124] Pagán AJ, Peters NC, Debrabant A, Ribeiro-Gomes F, Pepper M, Karp CL, et al. Tracking antigen—specific CD4 + T cells throughout the course of chronic *Leishmania major* infection in resistant mice. European Journal of Immunology. 2013;**43**:427-438. DOI: 10.1002/ eji.201242715

[125] Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL. Vector transmission of Leishmania abrogates vaccine-induced protective immunity. PLoS Pathogens. 2009;**5**:e1000484. DOI: 10.1371/ journal.ppat.1000484

[126] Peters NC, Pagán AJ, Lawyer PG, Hand TW, Henrique Roma E, Stamper LW, et al. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T Cells that are required for protection against re-infection. PLoS Pathogens. 2014;**10**:e1004538. DOI: 10.1371/journal. ppat.1004538

[127] Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet J-P, et al. The relationship between Leishmaniasis and AIDS: The second 10 years. Clinical Microbiology Reviews. 2008;**21**:334-359. DOI: 10.1128/CMR.00061-07

[128] Bogdan C. Mechanisms and consequences of persistence of intracellular pathogens: Leishmaniasis as an example. Cellular Microbiology. 2008;**10**:1221-1234. DOI: 10.1111/ j.1462-5822.2008.01146.x

[129] Parmentier L, Cusini A, Müller N, Zangger H, Hartley M-A, Desponds C,

*Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis DOI: http://dx.doi.org/10.5772/intechopen.101160*

et al. Severe cutaneous leishmaniasis in a human immunodeficiency virus patient coinfected with *Leishmania braziliensis* and its endosymbiotic virus. The American Journal of Tropical Medicine and Hygiene. 2016;**94**: 840-843. DOI: 10.4269/ajtmh.15-0803

[130] Hohman LS, Peters NC. CD4+ T cell-mediated immunity against the phagosomal pathogen Leishmania: Implications for vaccination. Trends in Parasitology. 2019;**35**:423-435. DOI: 10.1016/j.pt.2019.04.002

[131] Nylén S, Gautam S. Immunological perspectives of leishmaniasis. Journal of Global Infectious Diseases. 2010;**2**:135. DOI: 10.4103/0974-777X.62876

[132] Okwor I, Mou Z, Liu D, Uzonna J. Protective immunity and vaccination against cutaneous leishmaniasis. Frontiers in Immunology. 2012;**3**:128. DOI: 10.3389/fimmu.2012.00128

[133] Peters NC, Bertholet S, Lawyer PG, Charmoy M, Romano A, Ribeiro-Gomes FL, et al. Evaluation of recombinant leishmania polyprotein plus glucopyranosyl lipid A stable emulsion vaccines against sand fly-transmitted *Leishmania major* in C57BL/6 mice. Journal of Immunology. 2012;**189**:4832- 4841 10.4049/jimmunol.1201676

[134] Fischer MR, Schermann AI, Twelkmeyer T, Lorenz B, Wegner J, Jonuleit H, et al. Humanized mice in cutaneous leishmaniasis—Suitability analysis of human PBMC transfer into immunodeficient mice. Experimental Dermatology. 2019;**28**:1087-1090. DOI: 10.1111/exd.13999

[135] Atayde VD, Aslan H, Townsend S, Hassani K, Kamhawi S, Olivier M. Exosome secretion by the parasitic protozoan Leishmania within the sand fly midgut. Cell Reports. 2015;**13**:957- 967. DOI: 10.1016/j.celrep.2015.09.058
