Background The emergence of antibiotic-resistant strains of Salmonella enterica serovar Typhi (S. Typhi), the etiologic agent of typhoid fever, has aggravated an already important public health problem and added new urgency to the development of more effective typhoid vaccines. To this end it is critical to better understand the induction of immunity to S. Typhi. CD8+ T cells are likely to play an important role in host defense against S. Typhi by several effector mechanisms, including killing of infected cells and IFN-γ secretion. However, how S. Typhi regulates the development of specific CD8+ responses in humans remains unclear. Recent studies in mice have shown that dendritic cells (DC) can either directly (upon uptake and processing of Salmonella) or indirectly (by bystander mechanisms) elicit Salmonella-specific CD8+ T cells. Methodology/Principal Findings We report here that upon infection with live S. Typhi, human DC produced high levels of pro-inflammatory cytokines IL-6, IL-8 and TNF-α, but low levels of IL-12 p70 and IFN-γ. In contrast, DC co-cultured with S. Typhi-infected cells, through suicide cross-presentation, uptake S. Typhi-infected human cells and release high levels of IFN-γ and IL-12p70, leading to the subsequent presentation of bacterial antigens and triggering the induction of memory T cells, mostly CD3+CD8+CD45RA？CD62L？ effector/memory T cells. Conclusions/Significance This study is the first to demonstrate the effect of S. Typhi on human DC maturation and on their ability to prime CD8+ cells and highlights the significance of these phenomena in eliciting adaptive immunity to S. Typhi.
References
[1]
Crump JA, Luby SP, Mintz ED (2004) The global burden of typhoid fever. Bull World Health Organ 82: 346–353.
[2]
Mitchell DH (1997) Ciprofloxacin-resistant Salmonella typhi: an emerging problem. Med J Aust 167: 172.
[3]
Rowe B, Ward LR, Threlfall EJ (1997) Multidrug-resistant Salmonella typhi: a worldwide epidemic. Clin Infect Dis 24: Suppl 1S106–109.
[4]
Prost LR, Sanowar S, Miller SI (2007) Salmonella sensing of anti-microbial mechanisms to promote survival within macrophages. Immunol Rev 219: 55–65.
[5]
Salerno-Goncalves R, Pasetti MF, Sztein MB (2002) Characterization of CD8(+) Effector T Cell Responses in Volunteers Immunized with Salmonella enterica Serovar Typhi Strain Ty21a Typhoid Vaccine. J Immunol 169: 2196–2203.
[6]
Salerno-Goncalves R, Wyant TL, Pasetti MF, Fernandez-Vina M, Tacket CO, et al. (2003) Concomitant Induction of CD4(+) and CD8(+) T Cell Responses in Volunteers Immunized with Salmonella enterica Serovar Typhi Strain CVD 908-htrA. J Immunol 170: 2734–2741.
[7]
Sztein MB, Tanner MK, Polotsky Y, Orenstein JM, Levine MM (1995) Cytotoxic T lymphocytes after oral immunization with attenuated vaccine strains of Salmonella typhi in humans. J Immunol 155: 3987–3993.
[8]
Salerno-Goncalves R, Fernandez-Vina M, Lewinsohn DM, Sztein MB (2004) Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine. J Immunol 173: 5852–5862.
[9]
Salerno-Goncalves R, Wahid R, Sztein MB (2005) Immunization of volunteers with Salmonella enterica serovar Typhi strain Ty21a elicits the oligoclonal expansion of CD8+ T cells with predominant Vbeta repertoires. Infect Immun 73: 3521–3530.
[10]
Sztein MB, Wasserman SS, Tacket CO, Edelman R, Hone D, et al. (1994) Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized with attenuated vaccine strains of Salmonella typhi. J Infect Dis 170: 1508–1517.
[11]
Tacket CO, Galen J, Sztein MB, Losonsky G, Wyant TL, et al. (2000) Safety and immune responses to attenuated salmonella enterica serovar typhi oral live vector vaccines expressing tetanus toxin fragment C. Clin Immunol 97: 146–153.
[12]
Tacket CO, Pasetti MF, Sztein MB, Livio S, Levine MM (2004) Immune responses to an oral typhoid vaccine strain that is modified to constitutively express Vi capsular polysaccharide. J Infect Dis 190: 565–570. Epub 2004 Jun 2030.
[13]
Wahid R, Salerno-Goncalves R, Tacket CO, Levine MM, Sztein MB (2007) Cell-mediated immune responses in humans after immunization with one or two doses of oral live attenuated typhoid vaccine CVD 909. Vaccine 25: 1416–1425.
[14]
Wahid R, Salerno-Goncalves R, Tacket CO, Levine MM, Sztein MB (2008) Generation of specific effector and memory T cells with gut- and secondary lymphoid tissue- homing potential by oral attenuated CVD 909 typhoid vaccine in humans. Mucosal Immunology 1: 389–398.
[15]
Banchereau J, Palucka AK (2005) Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 5: 296–306.
[16]
Sundquist M, Rydstrom A, Wick MJ (2004) Immunity to Salmonella from a dendritic point of view. Cell Microbiol 6: 1–11.
[17]
Albert ML (2004) Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4: 223–231.
Heath WR, Belz GT, Behrens GM, Smith CM, Forehan SP, et al. (2004) Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev 199: 9–26.
[20]
Rock KL, Shen L (2005) Cross-presentation: underlying mechanisms and role in immune surveillance. Immunol Rev 207: 166–183.
[21]
Salerno-Goncalves R, Sztein MB (2006) Cell-mediated immunity and the challenges for vaccine development. Trends Microbiol 14: 536–542.
[22]
Pasetti MF, Levine MM, Sztein MB (2003) Animal models paving the way for clinical trials of attenuated Salmonella enterica serovar Typhi live oral vaccines and live vectors. Vaccine 21: 401–418.
[23]
Dunstan SJ, Ho VA, Duc CM, Lanh MN, Phuong CX, et al. (2001) Typhoid fever and genetic polymorphisms at the natural resistance-associated macrophage protein 1. J Infect Dis 183: 1156–1160.
[24]
Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392: 245–252.
[25]
Arrighi JF, Rebsamen M, Rousset F, Kindler V, Hauser C (2001) A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J Immunol 166: 3837–3845.
[26]
Svensson M, Johansson C, Wick MJ (2000) Salmonella enterica serovar typhimurium-induced maturation of bone marrow-derived dendritic cells. Infect Immun 68: 6311–6320.
[27]
Lanzavecchia A, Sallusto F (2001) The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 13: 291–298.
[28]
Mastroeni P, Harrison JA, Robinson JH, Clare S, Khan S, et al. (1998) Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent salmonellae in BALB/c mice: role of gamma interferon and macrophage activation. Infect Immun 66: 4767–4776.
[29]
Hess J, Ladel C, Miko D, Kaufmann SH (1996) Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-alpha beta cells and IFN-gamma in bacterial clearance independent of intracellular location. J Immunol 156: 3321–3326.
[30]
MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, et al. (2004) Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis 190: 1755–1757.
[31]
Stoycheva M, Murdjeva M (2005) Serum levels of interferon-gamma, interleukin-12, tumour necrosis factor-alpha, and interleukin-10, and bacterial clearance in patients with gastroenteric Salmonella infection. Scand J Infect Dis 37: 11–14.
[32]
Wick MJ (2003) The role of dendritic cells in the immune response to Salmonella. Immunol Lett 85: 99–102.
[33]
Chen LM, Kaniga K, Galan JE (1996) Salmonella spp. are cytotoxic for cultured macrophages. Mol Microbiol 21: 1101–1115.
[34]
Monack DM, Raupach B, Hromockyj AE, Falkow S (1996) Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc Natl Acad Sci U S A 93: 9833–9838.
[35]
Grant AJ, Sheppard M, Deardon R, Brown SP, Foster G, et al. (2008) Caspase-3-dependent phagocyte death during systemic Salmonella enterica serovar Typhimurium infection of mice. Immunology 125: 28–37.
[36]
Richter-Dahlfors A, Buchan AM, Finlay BB (1997) Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J Exp Med 186: 569–580.
[37]
Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, et al. (2003) Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424: 88–93.
[38]
Schakel K, Mayer E, Federle C, Schmitz M, Riethmuller G, et al. (1998) A novel dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb (M-DC8) and in vitro priming of cytotoxic T lymphocytes. Eur J Immunol 28: 4084–4093.
[39]
Marriott I, Hammond TG, Thomas EK, Bost KL (1999) Salmonella efficiently enter and survive within cultured CD11c+ dendritic cells initiating cytokine expression. Eur J Immunol 29: 1107–1115.
[40]
Rovere P, Vallinoto C, Bondanza A, Crosti MC, Rescigno M, et al. (1998) Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol 161: 4467–4471.
[41]
Wong KL, Lew FC, Macary PA, Kemeny DM (2008) CD40L-expressing CD8 T cells prime CD8alpha(+) DC for IL-12p70 production. Eur J Immunol 38: 2251–2262.
[42]
Yrlid U, Wick MJ (2000) Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 191: 613–624.
[43]
Guermonprez P, Amigorena S (2005) Pathways for antigen cross presentation. Springer Semin Immunopathol 26: 257–271.
[44]
Kurts C, Miller JF, Subramaniam RM, Carbone FR, Heath WR (1998) Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 188: 409–414.
