Coinfection with Heligmosomoides polygyrus Fails To Establish CD8+ T-Cell Immunity against Toxoplasma gondii

CD8 (cid:1) T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN- (cid:2) ), is essential for the development of primary CD8 (cid:1) T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN- (cid:2) levels fail to develop robust CD8 (cid:1) T-cell immunity against T. gondii . In the present study, induction of primary CD8 (cid:1) T-cell immune response against T. gondii infection was evaluated in mice infected earlier with Heligmosomoides polygyrus , a gastrointestinal worm known to evoke a polarized Th2 response in the host. In the early stage of T. gondii infection, both CD4 and CD8 (cid:1) T-cell responses against the parasite were suppressed in the dually infected mice. At the later stages, however, T. gondii -specific CD4 (cid:1) T-cell immunity recovered, while CD8 (cid:1) T-cell responses remained low. Unlike in mice infected with T. gondii alone, depletion of CD4 (cid:1) T cells in the dually infected mice led to reactivation of chronic infection, leading to Toxoplasma -related encephalitis. Our observations strongly suggest that prior infection with a Th2 cytokine-polarizing pathogen can inhibit the development of CD8 (cid:1) T-cell immune response against T. gondii , thus compromising long-term protection against a protozoan parasite. This is the first study to examine the generation of CD8 (cid:1) T-cell immune response in a parasitic nematode and protozoan coinfection model that has important implications for infections where a CD8 (cid:1) T-cell response is critical for host protection and reduced infection pathology.

[1]  K. Tanaka,et al.  Protection from lethal infection by adoptive transfer of CD8 T cells genetically engineered to express virus-specific innate immune receptor. , 2007, The Journal of Immunology.

[2]  H. Dawson,et al.  Infection with parasitic nematodes confounds vaccination efficacy. , 2007, Veterinary parasitology.

[3]  D. Elliott,et al.  Heligmosomoides polygyrus Promotes Regulatory T-Cell Cytokine Production in the Murine Normal Distal Intestine , 2007, Infection and Immunity.

[4]  R. Maizels,et al.  Expansion and activation of CD4+CD25+ regulatory T cells in Heligmosomoides polygyrus infection , 2007, European journal of immunology.

[5]  I. Khan,et al.  NK Cells Enhance Dendritic Cell Response against Parasite Antigens via NKG2D Pathway1 , 2007, The Journal of Immunology.

[6]  C. Piccirillo,et al.  Impairment of dendritic cell function by excretory‐secretory products: A potential mechanism for nematode‐induced immunosuppression , 2007, European journal of immunology.

[7]  S. Way,et al.  Cutting Edge: Recombinant Listeria monocytogenes Expressing a Single Immune-Dominant Peptide Confers Protective Immunity to Herpes Simplex Virus-1 Infection1 , 2007, The Journal of Immunology.

[8]  I. Duce,et al.  Human gastrointestinal nematode infections: are new control methods required? , 2006, International journal of experimental pathology.

[9]  Alessandro Sette,et al.  CD8+ T-Cell Responses to Trypanosoma cruzi Are Highly Focused on Strain-Variant trans-Sialidase Epitopes , 2006, PLoS pathogens.

[10]  D. Elliott,et al.  Induction of CD8+ regulatory T cells in the intestine by Heligmosomoides polygyrus infection. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[11]  C. Klebanoff,et al.  CD8+ T‐cell memory in tumor immunology and immunotherapy , 2006, Immunological reviews.

[12]  J. Schwartzman,et al.  Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[13]  W. Walker,et al.  Helminth-Primed Dendritic Cells Alter the Host Response to Enteric Bacterial Infection1 , 2006, The Journal of Immunology.

[14]  R. Maizels,et al.  Suppression of allergic airway inflammation by helminth-induced regulatory T cells , 2005, The Journal of experimental medicine.

[15]  T. Curiel,et al.  NK Cells Help To Induce CD8+-T-Cell Immunity against Toxoplasma gondii in the Absence of CD4+ T Cells , 2005, Infection and Immunity.

[16]  R. Miller,et al.  IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques. , 2004, Vaccine.

[17]  O. Liesenfeld,et al.  Infection with Toxoplasma gondii Reduces Established and Developing Th2 Responses Induced by Nippostrongylus brasiliensis Infection , 2004, Infection and Immunity.

[18]  A. L. La Flamme,et al.  Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis , 2003, Infection and Immunity.

[19]  P. Andersen,et al.  An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen1 , 2002, The Journal of Immunology.

[20]  J. Sprent,et al.  Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells , 2002, The Journal of experimental medicine.

[21]  J. Schwartzman,et al.  Treatment with Soluble Interleukin-15Rα Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response , 2002, The Journal of experimental medicine.

[22]  T. Nolan,et al.  Infection of mice with the helminth Strongyloides stercoralis suppresses pulmonary allergic responses to ovalbumin , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  J. Schwartzman,et al.  IP-10 is critical for effector T cell trafficking and host survival in Toxoplasma gondii infection. , 2000, Immunity.

[24]  R. McLeod,et al.  Measurement of the efficacy of vaccines and antimicrobial therapy against infection with Toxoplasma gondii. , 2000, International journal for parasitology.

[25]  J. Schwartzman,et al.  Immune CD8+ T Cells Prevent Reactivation of Toxoplasma gondii Infection in the Immunocompromised Host , 1999, Infection and Immunity.

[26]  I. Khan,et al.  IL-15 prolongs the duration of CD8+ T cell-mediated immunity in mice infected with a vaccine strain of Toxoplasma gondii. , 1999, Journal of immunology.

[27]  E. Pearce,et al.  Toxoplasma gondii and Schistosoma mansoni synergize to promote hepatocyte dysfunction associated with high levels of plasma TNF-alpha and early death in C57BL/6 mice. , 1999, Journal of immunology.

[28]  I. Khan,et al.  Augmentation of the CD8+ T cell response by IFN-gamma in IL-12-deficient mice during Toxoplasma gondii infection. , 1999, Journal of immunology.

[29]  A. Cooke,et al.  Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non‐obese diabetic mice , 1999, Parasite immunology.

[30]  J. Schwartzman,et al.  A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  I. Khan,et al.  IL-15 augments CD8+ T cell-mediated immunity against Toxoplasma gondii infection in mice. , 1996, Journal of immunology.

[32]  Y. Suzuki,et al.  Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii , 1996, The Journal of experimental medicine.

[33]  I. Khan,et al.  IL-7 stimulates protective immunity in mice against the intracellular pathogen, Toxoplasma gondii. , 1995, Journal of immunology.

[34]  A. Ben-Smith,et al.  Immunological relationships during primary infection with Heligmosomoides polygyrus: Th2 cytokines and primary response phenotype , 1994, Parasitology.

[35]  F. Finkelman,et al.  A primary intestinal helminthic infection rapidly induces a gut-associated elevation of Th2-associated cytokines and IL-3. , 1993, Journal of immunology.

[36]  J. Behnke,et al.  Stimuli for acquired resistance to Heligmosomoides polygyrus from intestinal tissue resident L3 and L4 larvae. , 1992, International journal for parasitology.

[37]  A. Sher,et al.  Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. , 1992, Journal of immunology.

[38]  J. Berzofsky,et al.  Infection with Schistosoma mansoni alters Th1/Th2 cytokine responses to a non-parasite antigen. , 1992, Journal of immunology.

[39]  J. Remington,et al.  Murine CD8+ cytotoxic T lymphocytes lyse Toxoplasma gondii-infected cells. , 1991, Journal of immunology.

[40]  C. Roberts,et al.  CD8+ T cells are the major lymphocyte subpopulatlon involved in the protective immune response to Toxoplasma gondii in mice , 1991, Clinical and experimental immunology.

[41]  A. Sher,et al.  Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. , 1991, Journal of immunology.

[42]  R. McLeod,et al.  Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection. , 1990, Journal of immunology.

[43]  J. Boothroyd,et al.  Direct and sensitive detection of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain reaction , 1989, Journal of clinical microbiology.

[44]  V. Barnett,et al.  Applied Linear Statistical Models , 1975 .

[45]  R. V. van Lier,et al.  Induction and maintenance of CD8+ T cells specific for persistent viruses. , 2007, Advances in experimental medicine and biology.