Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections

DOI: 10.4236/oji.2012.21004   PDF   HTML     4,188 Downloads   8,338 Views   Citations


We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T cells. To further understand the function of T-CD4 T cells, we investigated immune responses mediated by T-CD4 T cells during bacterial infection because the generation of antigen specific CD4 T cells contributes to clearance of infection and for the development of immune memory. The current study shows a suppressive effect of T-CD4 T cells on both CD8 and CD4 T cell-mediated immune responses during Listeria and Helicobacter infections. In the mouse model of Listeria monocytogenes infection, T-CD4 T cells resulted in decreasedfrequency of Listeria-specific CD8 T cells and the killing activity of them. Furthermore, mice with T-CD4 T cells developed poor immune memory, demonstrated by reduced expansion of antigen-specific T cells and high bacterial burden upon re-infection. Similarly, the presence of T-CD4 T cells suppressed the generation of antigen-specific CD4 T cells in Helicobacter pylori infected mice. Thus, our studies reveal a novel function of T-CD4 T cells in sup-pressing anti-bacterial immunity.

Share and Cite:

Qiao, Y. , Gray, B. , Sofi, M. , Bauler, L. , Eaton, K. , O’Riordan, M. and Chang, C. (2012) Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections. Open Journal of Immunology, 2, 25-39. doi: 10.4236/oji.2012.21004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Germain, R.N. (2002) T-cell development and the CD4-CD8 lineage decision. Nature Reviews Immunology, 2, 309-322. doi:10.1038/nri798
[2] Bonduel, M., Pozo, A., Zelazko, M., Raslawski, E., Delfino, S., Rossi, J., Figueroa, C. and Sackmann, M.F. (1999) Successful related umbilical cord blood transplantation for graft failure following T cell-depleted non-identical bone marrow transplantation in a child with major histocompatibility complex class II deficiency. Bone Marrow Transplant, 24, 437-440. doi:10.1038/sj.bmt.1701915
[3] Godthelp, B.C., van Eggermond, M.C., Peijnenburg, A., Tezcan, I., van Lierde, S., van Tol, M.J., Vossen, J.M. and van den Elsen, P.J. (1999) Incomplete T-cell immune reconstitution in two major histocompatibility complex class II-deficiency/bare lymphocyte syndrome patients after HLA-identical sibling bone marrow transplantation. Blood, 94, 348-358.
[4] Klein, C., Cavazzana-Calvo, M., Le Deist, F., Jabado, N., Benkerrou, M., Blanche, S., Lisowska-Grospierre, B., Griscelli, C. and Fischer, A. (1995) Bone marrow transplantation in major histocompatibility complex class II deficiency: A single-center study of 19 patients. Blood, 85, 580-587.
[5] De Smedt, M., Hoebeke, I. and Plum, J. (2004) Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment. Blood Cells, Molecules, and Diseases, 33, 227-232. doi:10.1016/j.bcmd.2004.08.007
[6] Lee, Y.J., Jeon, Y.K., Kang, B.H., Chung, D.H., Park, C.G., Shin, H.Y., Jung, K.C. and Park, S.H. (2010) Generation of PLZF+ CD4+ T cells via MHC class II-dependent thymocyte-thymocyte interaction is a physiological process in humans. The Journal of Experimental Medicine, 207, 237-246
[7] Van Coppernolle, S., Verstichel, G., Timmermans, F., Velghe, I., Vermijlen, D., De Smedt, M., Leclercq, G., Plum, J., Taghon, T., Vandekerckhove, B. and Kerre, T. (2009) Functionally mature CD4 and CD8 TCRalphabeta cells are generated in OP9-DL1 cultures from human CD34+ hematopoietic cells. Journal of Immunology, 183, 4859-4870. doi:10.4049/jimmunol.0900714
[8] Choi, E.Y., Jung, K.C., Park, H.J., Chung, D.H., Song, J.S., Yang, S.D., Simpson, E. and Park, S.H. (2005) Thymocyte-thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity, 23, 387-396. doi:10.1016/j.immuni.2005.09.005
[9] Li, W., Kim, M.G., Gourley, T.S., McCarthy, B.P., Sant’ Angelo, D.B. and Chang, C.H. (2005) An alternate pathway for CD4 T cell development: Thymocyte-expressed MHC class II selects a distinct T cell population. Immunity, 23, 375-86. doi:10.1016/j.immuni.2005.09.002
[10] Zhu, J. and Paul, W.E. (2010) Heterogeneity and plasticity of T helper cells. Cell Research, 20, 4-12. doi:10.1038/cr.2009.138
[11] Elgueta, R., de Vries, V.C. andNoelle, R.J. (2010) The immortality of humoral immunity. The Immunological Reviews, 236, 139-150. doi:10.1111/j.1600-065X.2010.00924.x
[12] Annunziato, F., Cosmi, L., Santarlasci, V., Maggi, L., Liotta, F., Mazzinghi, B., Parente, E., Fili, L., Ferri, S., Frosali, F., Giudici, F., Romagnani, P., Parronchi, P., Tonelli, F., Maggi, E. and Romagnani, S. (2007) Phenotypic and functional features of human Th17 cells. The Jouranl of Experimental Medicine, 204, 1849-1861. doi:10.1084/jem.20070663
[13] Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L. and Kuchroo, V.K. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235-238. doi:10.1038/nature04753
[14] Vokaer, B., Van Rompaey, N., Lemaitre, P.H., Lhomme, F., Kubjak, C., Benghiat, F.S., Iwakura, Y., Petein, M., Field, K.A., Goldman, M., Le Moine, A. and Charbonnier, L.M. (2010) Critical role of regulatory T cells in Th17-mediated minor antigen-disparate rejection. Journal of Immunology, 185, 3417-3425. doi:10.4049/jimmunol.0903961
[15] Crotty, S., Kersh, E.N., Cannons, J., Schwartzberg, P.L. and Ahmed, R. (2003) SAP is required for generating long-term humoral immunity. Nature, 421, 282-287. doi:10.1038/nature01318
[16] Janssen, E.M., Droin NM, Lemmens, E.E., Pinkoski, M.J., Bensinger, S.J., Ehst, B.D., Griffith, T.S., Green, D.R. and Schoenberger, S.P. (2005) CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature, 434, 88-93. doi:10.1038/nature03337
[17] Janssen, E.M., Lemmens, E.E., Wolfe, T., Christen, U., von Herrath, M.G. and Schoenberger, S.P. (2003) CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature, 421, 852-856. doi:10.1038/nature01441
[18] Shedlock, D.J. and Shen, H. (2003) Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science, 300, 337-339. doi:10.1126/science.1082305
[19] Sun, J.C. and Bevan, M.J. (2003) Defective CD8 T cell memory following acute infection without CD4 T cell help. Science, 300, 339-342. doi:10.1126/science.1083317
[20] Vieira, P. and Rajewsky, K. (1990) Persistence of memory B cells in mice deprived of T cell help. International Immunology, 2, 487-494. doi:10.1093/intimm/2.6.487
[21] Li, W., Sofi, M.H., Yeh, N., Sehra, S., McCarthy, B.P., Patel, D.R., Brutkiewicz, R.R., Kaplan, M.H. andChang, C.H. (2007) Thymic selection pathway regulates the effector function of CD4 T cells. The Jouranl of Experimental Medicine, 204, 2145-57. doi:10.1084/jem.20070321
[22] Bendelac, A., Killeen, N., Littman, D.R. andSchwartz, R.H. (1994) A subset of CD4+ thymocytes selected by MHC class I molecules. Science, 263, 1774-1778. doi:10.1126/science.7907820
[23] Budd, R.C., Miescher, G.C., Howe, R.C., Lees, R.K., Bron, C. and MacDonald, H.R. (1987) Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes. The Jouranl of Experimental Medicine, 166, 577-582. doi:10.1084/jem.166.2.577
[24] Fowlkes, B.J., Kruisbeek, A.M., Ton-That, H., Weston, M.A., Coligan, J.E., Schwartz, R.H. and Pardoll, D.M. (1987) A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature, 329, 251-254. doi:10.1038/329251a0
[25] Gapin, L., Matsuda, J.L., Surh, C.D. and Kronenberg, M. (2001) NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nature Immunology, 2, 971-978. doi:10.1038/ni710
[26] Sofi, M.H., Liu, Z., Zhu, L., Yu, Q., Kaplan, M.H. and-Chang, C.H. (2010) Regulation of IL-17 expression by the developmental pathway of CD4 T cells in the thymus. Molecular Immunology, 47, 1262-1268. doi:10.1016/j.molimm.2009.12.010
[27] Park, J.H., Chang, S.H., Kim, M.C., Shin, S.H., Youn, H.J., Kim, J.K., Jang, Y.S. and Kim, C.W. (1998) Up-regulation of the expression of major histocompatibility complex class I antigens by plasmid DNA transfection in non-hematopoietic cells. FEBS Letters, 436, 55-60. doi:10.1016/S0014-5793(98)01097-7
[28] Portnoy, D.A. and Jones, S. (1994) The cell biology of Listeria monocytogenes infection (escape from a vacuole). Annals of the New York Academy of Science, 730, 15-25. doi:10.1111/j.1749-6632.1994.tb44235.x
[29] Portnoy, D.A., Auerbuch, V. and Glomski, I.J. (2002) The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. The Journal of Cell Biology, 158, 409-414. doi:10.1083/jcb.200205009
[30] Zwickey, H.L. and Potter, T.A. (1999) Antigen secreted from noncytosolic Listeria monocytogenes is processed by the classical MHC class I processing pathway. Journal of Immunology, 162, 6341-6350.
[31] Harty, J.T. and White, D. (1999) A knockout approach to understanding CD8+ cell effector mechanisms in adaptive immunity to Listeria monocytogenes. Immunobiology, 201, 196-204.
[32] Buchmeier, N.A. andSchreiber, R.D. (1985) Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proceedings of the National Academy of Sciences USA, 82, 7404-7408. doi:10.1073/pnas.82.21.7404
[33] Basham, T., Smith, W., Lanier, L., Morhenn, V. and Merigan, T. (1984) Regulation of expression of class II major histocompatibility antigens on human peripheral blood monocytes and Langerhans cells by interferon. Human Immunology, 10, 83-93. doi:10.1016/0198-8859(84)90075-2
[34] Finelli, A., Kerksiek, K.M., Allen, S.E., Marshall, N., Mercado, R., Pilip, I., Busch, D.H. andPamer, E.G. (1999) MHC class I restricted T cell responses to Listeria mono-cytogenes, an intracellular bacterial pathogen. Immunologic Research, 19, 211-223. doi:10.1007/BF02786489
[35] Kagi, D., Ledermann, B., Burki, K., Hengartner, H. and Zinkernagel, R.M. (1994) CD8+ T cell-mediated protecttion against an intracellular bacterium by perforin-dependent cytotoxicity. European Journal of Immunology, 24, 3068-3072. doi:10.1002/eji.1830241223
[36] Smith, C.M., Wilson, N.S., Waithman, J., Villadangos, J.A., Carbone, F.R., Heath, W.R. andBelz, G.T. (2004) Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nature Immunology, 5, 1143-1148. doi:10.1038/ni1129
[37] Sun, J.C., Williams, M.A. and Bevan, M.J. (2004) CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunology, 5, 927-933. doi:10.1038/ni1105
[38] Shedlock, D.J., Whitmire, J.K., Tan, J., MacDonald, A.S., Ahmed, R. and Shen, H. (2003) Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. Journal of Immunology, 170, 2053-2063.
[39] Eaton, K.A., Mefford, M. and Thevenot, T. (2001) The role of T cell subsets and cytokines in the pathogenesis of helicobacter pylori gastritis in mice. Journal of Immunology, 166, 7456-7461.
[40] Eaton, K.A., Ringler, S.R. and Danon, S.J. (1999) Murine splenocytes induce severe gastritis and delayed-type hypersensitivity and suppress bacterial colonization in Helicobacter pylori-infected SCID mice. Infection and Immunity, 67, 4594-4602.
[41] D’Elios, M.M., Manghetti, M., De Carli, M., Costa, F., Baldari, C.T., Burroni, D., Telford, J.L., Romagnani, S. and Del Prete, G. (1997) T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. Journal of Immunology, 158, 962-967.
[42] Smythies, L.E., Waites, K.B., Lindsey, J.R., Harris, P.R., Ghiara, P. and Smith, P.D. (2000) Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice. Journal of Immunology, 165, 1022-1029.
[43] Eaton, K., Benson, L., Haeger, J., Gray, B. (2006) Role of transcription factor T-bet expression by CD4+ cells in gastritis due to Helicobacter pylori in mice. Infection and Immunity, 74, 4673-4684. doi:10.1128/IAI.01887-05
[44] Pope, C., Kim, S.K., Marzo, A., Masopust, D., Williams, K., Jiang, J., Shen, H. andLefrancois, L. (2001) Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. Journal of Immunology, 166, 3402-3409.
[45] Sofi, M.H., Qiao, Y., Ansel, K.M., Kubo, M. andChang, C.H. (2011) Induction and maintenance of IL-4 expression are regulated differently by the 3' enhancer in CD4 T cells. Journal of Immunology, 186, 2792-2799. doi:10.4049/jimmunol.1003353
[46] Barber, D.L., Wherry, E.J. and Ahmed, R. (2003) Cutting edge: Rapid in vivo killing by memory CD8 T cells. Journal of Immunology, 171, 27-31.
[47] Beek, B. (1981) Cell proliferation and chromosomal damage in human leukocytes: Dicentrics and premature chromosome condensations in first, second, and third mitoses after X-irradiation. Human Genetics, 57, 75-77. doi:10.1007/BF00271172
[48] Roos, W.P. and Kaina, B. (2006) DNA damage-induced cell death by apoptosis. Trends in Molecular Medicine, 12, 440-450. doi:10.1016/j.molmed.2006.07.007
[49] Min, H.S., Lee, Y.J., Jeon, Y.K., Kim, E.J., Kang, B.H., Jung, K.C., Chang, C.H. and Park, S.H. (2011) MHC Class II-restricted interaction between thymocytes plays an essential role in the production of innate CD8 T cells. Journal of Immunology, 186, 5749-5757. doi:10.4049/jimmunol.1002825
[50] Park, W.S., Bae, Y., Chung, D.H., Choi, Y.L., Kim, B.K., Sung, Y.C., Choi, E.Y., Park, S.H. and Jung, K.C. (2004) T cell expression of CIITA represses Th1 immunity. International Immunology, 16, 1355-1364. doi:10.1093/intimm/dxh132
[51] Weinreich, M.A., Odumade, O.A., Jameson, S.C. and Hogquist, K.A. (2010) T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nature Immunology, 11, 709-716. doi:10.1038/ni.1898
[52] Verykokakis, M., Boos, M.D., Bendelac, A. and Kee, B.L. (2010) SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity, 33, 203-215. doi:10.1016/j.immuni.2010.07.013
[53] Caruso, R., Fina, D., Paoluzi, O.A., Del Vecchio Blanco, G., Stolfi, C., Rizzo, A., Caprioli, F., Sarra, M., Andrei, F., Fantini, M.C., MacDonald, T.T., Pallone, F. and Monteleone, G. (2008) IL-23-mediated regulation of IL-17 production in Helicobacter pylori-infected gastric mucosa. European Journal of Immunology, 38, 470-478. doi:10.1002/eji.200737635
[54] Mizuno, T., Ando, T., Nobata, K., Tsuzuki, T., Maeda, O., Watanabe, O., Minami, M., Ina, K., Kusugami, K., Peek, R.M. and Goto, H. (2005) Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization. World Journal of Gastroenterology, 11, 6305-6311.
[55] Eaton, K.A., Ringler, S.R. and Danon, S.J. (1999) Murine splenocytes induce severe gastritis and delayed-type hypersensitivity and suppress bacterial colonization in Helicobacter pylori-infected SCID mice. Infection and Immunity, 67, 4594-4602.
[56] Matsumoto, Y., Blanchard, T.G., Drakes, M.L., Basu, M., Redline, R.W., Levine, A.D. and Czinn, S.J. (2005) Eradication of Helicobacter pylori and resolution of gastritis in the gastric mucosa of IL-10-deficient mice. Helicobacter, 10, 407-415. doi:10.1111/j.1523-5378.2005.00349.x
[57] Marshall, B.J. (1995) Helicobacter pylori in peptic ulcer: Have Koch’s postulates been fulfilled? Annals of Medicine, 27, 565-568. doi:10.3109/07853899509002470
[58] Wilson, K.T. and Crabtree, J.E. (2007) Immunology of Helicobacter pylori: Insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology, 133, 288-308. doi:10.1053/j.gastro.2007.05.008
[59] Park, S.H., Bae, Y.M., Kim, T.J., Ha, I.S., Kim, S.T., Chi, J.G. and Lee, S.K. (1992) HLA-DR expression in human fetal thymocytes. Human Immunology, 33, 294-298. doi:10.1016/0198-8859(92)90338-N
[60] Mold, J.E., Venkatasubrahmanyam, S., Burt, T.D., Micha?lsson, J., Rivera, J.M., Galkina, S.A., Weinberg, K., Stoddart, C.A. and McCune, J.M. (2010) Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science, 330, 1695-1699.
[61] PrabhuDas, M., Adkins, B., Gans, H., King, C., Levy, O., Ramilo, O. and Siegrist, C.A. (2011) Challenges in infant immunity: Implications for responses to infection and vaccines. Nature Immunology, 12, 189-194. doi:10.1038/ni0311-189
[62] Markert, M., Devlin, B., Alexieff, M., Li, J., McCarthy, E., Gupton, S., Chinn, I., Hale, L., Kepler, T., He, M., Sarzotti, M., Skinner, M., Rice, H. and Hoehner, J. (2007) Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood, 109, 4539-4547. doi:10.1182/blood-2006-10-048652
[63] Markert, M.L., Alexieff, M.J., Li, J., Sarzotti, M., Ozaki, D.A., Devlin, B.H., Sedlak, D.A., Sempowski, G.D., Hale, L.P., Rice, H.E., Mahaffey, S.M. and Skinner, M.A. (2004) Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood, 104, 2574-2581. doi:10.1182/blood-2003-08-2984
[64] Markert, M.L., Boeck, A., Hale, L.P., Kloster, A.L., Mc-Laughlin, T.M., Batchvarova, M.N., Douek, D.C., Koup, R.A., Kostyu, D.D., Ward, F.E., Rice, H.E., Mahaffey, S.M., Schiff, S.E., Buckley, R.H. and Haynes, B.F. (1999) Transplantation of thymus tissue in complete DiGeorge syndrome. The New England Journal of Medicine, 341, 1180-1189. doi:10.1056/NEJM199910143411603
[65] Markert, M.L., Sarzotti, M., Ozaki, D.A., Sempowski, G.D., Rhein, M.E., Hale, L.P., Le Deist, F., Alexieff, M.J., Li, J., Hauser, E.R., Haynes, B.F., Rice, H.E., Skinner, M.A., Mahaffey, S.M., Jaggers, J., Stein, L.D. and Mill, M.R. (2003) Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood, 102, 1121-1130. doi:10.1182/blood-2002-08-2545

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.