• 1
    Doherty, P. C., Topham, D. J., Tripp, R. A., Cardin, R. D., Brooks, J. W. and Stevenson, P. G., Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol. Rev. 1997. 159: 105117.
  • 2
    Bennett, S. R., Carbone, F. R., Karamalis, F., Flavell, R. A., Miller, J. F. and Heath, W. R., Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998. 393: 478480.
  • 3
    Ridge, J. P., Di Rosa, F. and Matzinger, P., A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 1998. 393: 474478.
  • 4
    Toes, R. E., Schoenberger, S. P., van der Voort, E. I., Offringa, R. and Melief, C. J., CD40-CD40Ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity. Semin. Immunol. 1998. 10: 443448.
  • 5
    Buhlmann, J. E., Gonzalez, M., Ginther, B., Panoskaltsis-Mortari, A., Blazar, B. R., Greiner, D. L., Rossini, A. A. et al., Cutting edge: sustained expansion of CD8+ T cells requires CD154 expression by Th cells in acute graft versus host disease. J. Immunol. 1999. 162: 43734376.
  • 6
    Belz, G. T., Wodarz, D., Diaz, G., Nowak, M. A. and Doherty, P. C., Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice. J. Virol. 2002. 76: 1238812393.
  • 7
    Sun, J. C. and Bevan, M. J., Defective CD8 T-cell memory following acute infection without CD4 T-cell help. Science 2003. 300: 339342.
  • 8
    Shedlock, D. J. and Shen, H., Requirement for CD4 T-cell help in generating functional CD8 T-cell memory. Science 2003. 300: 337339.
  • 9
    Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G. and Schoenberger, S. P., CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003. 421: 852856.
  • 10
    Lu, Z., Yuan, L., Zhou, X., Sotomayor, E., Levitsky, H. I. and Pardoll, D. M., CD40-independent pathways of T-cell help for priming of CD8(+) cytotoxic T lymphocytes. J. Exp. Med. 2000. 191: 541550.
  • 11
    Baker, P. E., Gillis, S., Ferm, M. M. and Smith, K. A., The effect of T-cell growth factor on the generation of cytolytic T cells. J. Immunol. 1978. 121: 21682173.
  • 12
    Wagner, H. and Rollinghoff, M., T-T-cell interactions during the vitro cytotoxic allograft responses. I. Soluble products from activated Lyl+ T cells trigger autonomously antigen-primed Ly23+ T cells to cell proliferation and cytolytic activity. J. Exp. Med. 1978. 148: 15231538.
  • 13
    Mueller, S. N., Jones, C. M., Stock, A. T., Suter, M., Heath, W. R. and Carbone, F. R., CD4+ T cells can protect APC from CTL-mediated elimination. J. Immunol. 2006. 176: 73797384.
  • 14
    Allan, W., Tabi, Z., Cleary, A. and Doherty, P. C., Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J. Immunol. 1990. 144: 39803986.
  • 15
    Bodmer, H., Obert, G., Chan, S., Benoist, C. and Mathis, D., Environmental modulation of the autonomy of cytotoxic T lymphocytes. Eur. J. Immunol. 1993. 23: 16491654.
  • 16
    Tripp, R. A., Sarawar, S. R. and Doherty, P. C., Characteristics of the influenza virus-specific CD8+ T-cell response in mice homozygous for disruption of the H-2lAb gene. J. Immunol. 1995. 155: 29552959.
  • 17
    Mozdzanowska, K., Maiese, K. and Gerhard, W., Th cell-deficient mice control influenza virus infection more effectively than Th- and B cell-deficient mice: evidence for a Th-independent contribution by B cells to virus clearance. J. Immunol. 2000. 164: 26352643.
  • 18
    Ahmed, R., Butler, L. D. and Bhatti, L., T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J. Virol. 1988. 62: 21022106.
  • 19
    Rahemtulla, A., Fung-Leung, W. P., Schilham, M. W., Kundig, T. M., Sambhara, S. R., Narendran, A., Arabian, A. et al., Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 1991. 353: 180184.
  • 20
    Mizuochi, T., Hugin, A. W., Morse, H. C., 3rd, Singer, A. and Buller, R. M., Role of lymphokine-secreting CD8+ T cells in cytotoxic T lymphocyte responses against vaccinia virus. J. Immunol. 1989. 142: 270273.
  • 21
    Johnson, S., Zhan, Y., Sutherland, R. M., Mount, A. M., Bedoui, S., Brady, J. L., Carrington, E. M. et al., Selected Toll-like receptor ligands and viruses promote helper-independent cytotoxic T-cell priming by upregulating CD40L on dendritic cells. Immunity 2009. 30: 218227.
  • 22
    Wiesel, M., Kratky, W. and Oxenius, A., Type I IFN substitutes for T-cell help during viral infections. J. Immunol. 2011. 186: 754763.
  • 23
    Boesteanu, A. C. and Katsikis, P. D., Memory T cells need CD28 costimulation to remember. Semin. Immunol. 2009. 21: 6977.
  • 24
    Shahinian, A., Pfeffer, K., Lee, K. P., Kundig, T. M., Kishihara, K., Wakeham, A., Kawai, K. et al., Differential T-cell costimulatory requirements in CD28-deficient mice. Science 1993. 261: 609612.
  • 25
    Suresh, M., Whitmire, J. K., Harrington, L. E., Larsen, C. P., Pearson, T. C., Altman, J. D. and Ahmed, R., Role of CD28-B7 interactions in generation and maintenance of CD8 T-cell memory. J. Immunol. 2001. 167: 55655573.
  • 26
    Kundig, T. M., Shahinian, A., Kawai, K., Mittrucker, H. W., Sebzda, E., Bachmann, M. F., Mak, T. W. et al., Duration of TCR stimulation determines costimulatory requirement of T cells. Immunity 1996. 5: 4152.
  • 27
    Andreasen, S. O., Christensen, J. E., Marker, O. and Thomsen, A. R., Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T-cell responses. J. Immunol. 2000. 164: 36893697.
  • 28
    Borrow, P., Tishon, A., Lee, S., Xu, J., Grewal, I. S., Oldstone, M. B. and Flavell, R. A., CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J. Exp. Med. 1996. 183: 21292142.
  • 29
    Whitmire, J. K., Slifka, M. K., Grewal, I. S., Flavell, R. A. and Ahmed, R., CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection. J. Virol. 1996. 70: 83758381.
  • 30
    Lumsden, J. M., Roberts, J. M., Harris, N. L., Peach, R. J. and Ronchese, F., Differential requirement for CD80 and CD80/CD86-dependent costimulation in the lung immune response to an influenza virus infection. J. Immunol. 2000. 164: 7985.
  • 31
    Bertram, E. M., Dawicki, W. and Watts, T. H., Role of T-cell costimulation in anti-viral immunity. Semin. Immunol. 2004. 16: 185196.
  • 32
    Mescher, M. F., Curtsinger, J. M., Agarwal, P., Casey, K. A., Gerner, M., Hammerbeck, C. D., Popescu, F. et al., Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 2006. 211: 8192.
  • 33
    Vincenti, F., Dritselis, A. and Kirkpatrick, P., Belatacept. Nat. Rev. Drug Discov. 2011. 10: 655656.
  • 34
    Wells, A. F., Westhovens, R., Reed, D. M., Fanti, L., Becker, J. C., Covucci, A. and Keystone, E. C., Abatacept plus methotrexate provides incremental clinical benefits versus methotrexate alone in methotrexate-naive patients with early rheumatoid arthritis who achieve radiographic nonprogression. J. Rheumatol. 2011. 38: 23622368.
  • 35
    Wojciechowski, D. and Vincenti, F., Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation. Semin. Immunol. 2011. 23: 157164.
  • 36
    Wiley, J. A., Hogan, R. J., Woodland, D. L. and Harmsen, A. G., Antigen-specific CD8(+) T cells persist in the upper respiratory tract following influenza virus infection. J. Immunol. 2001. 167: 32933299.
  • 37
    Han, W. R., Zhan, Y., Murray-Segal, L. J., Brady, J. L., Lew, A. M. and Mottram, P. L., Prolonged allograft survival in anti-CD4 antibody transgenic mice: lack of residual helper T cells compared with other CD4-deficient mice. Transplantation 2000. 70: 168174.
  • 38
    Zhan, Y., Brown, L. E., Deliyannis, G., Seah, S., Wijburg, O. L., Price, J., Strugnell, R. A. et al., Responses against complex antigens in various models of CD4 T-cell deficiency: surprises from an anti-CD4 antibody transgenic mouse. Immunol. Res. 2004. 30: 114.
  • 39
    La Gruta, N. L., Rothwell, W. T., Cukalac, T., Swan, N. G., Valkenburg, S. A., Kedzierska, K., Thomas, P. G. et al., Primary CTL response magnitude in mice is determined by the extent of naive T-cell recruitment and subsequent clonal expansion. J. Clin. Invest. 2010. 120: 18851894.
  • 40
    Seah, S. G., Sutherland, R. M., La Gruta, N. L., Brown, L. E., Carrington, E. M., Belz, G. T., Brady, J. L. et al., The linear range for accurately quantifying antigen-specific T-cell frequencies by tetramer staining during natural immune responses. Eur. J. Immunol. 2011. 41: 14991500.
  • 41
    Behrens, G., Li, M., Smith, C. M., Belz, G. T., Mintern, J., Carbone, F. R. and Heath, W. R., Helper T cells, dendritic cells and CTL Immunity. Immunol. Cell Biol. 2004. 82: 8490.
  • 42
    Hamilton, S. E., Tvinnereim, A. R. and Harty, J. T., Listeria monocytogenes infection overcomes the requirement for CD40 ligand in exogenous antigen presentation to CD8(+) T cells. J. Immunol. 2001. 167: 56035609.
  • 43
    Buller, R. M., Holmes, K. L., Hugin, A., Frederickson, T. N. and Morse, H. C., 3rd, Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 1987. 328: 7779.
  • 44
    Ruedl, C., Kopf, M. and Bachmann, M. F., CD8(+) T cells mediate CD40-independent maturation of dendritic cells in vivo. J. Exp. Med. 1999. 189: 18751884.
  • 45
    Zimmerli, S. C., Harari, A., Cellerai, C., Vallelian, F., Bart, P. A. and Pantaleo, G., HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc. Natl. Acad. Sci. USA 2005. 102: 72397244.
  • 46
    Sun, J. C. and Bevan, M. J., Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J. Immunol. 2004. 172: 33853389.
  • 47
    Smith, C. M., Wilson, N. S., Waithman, J., Villadangos, J. A., Carbone, F. R., Heath, W. R. and Belz, G. T., Cognate CD4(+) T-cell licensing of dendritic cells in CD8(+) T-cell immunity. Nat. Immunol. 2004. 5: 11431148.
  • 48
    Cinque, P., Vago, L., Marenzi, R., Giudici, B., Weber, T., Corradini, R., Ceresa, D. et al., Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid. Clin. Infect. Dis. 1998. 27: 303309.
  • 49
    Sheth, A. N., Althoff, K. N. and Brooks, J. T., Influenza susceptibility, severity, and shedding in HIV-Infected adults: a review of the literature. Clin. Infect. Dis. 2011. 52: 219227.
  • 50
    The-Kaiser-Foundation, Reporting Manual on HIV/AIDS 2005: 1-50.
  • 51
    Bertram, E. M., Lau, P. and Watts, T. H., Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T-cell numbers late in the primary response and regulates the size of the T-cell memory response following influenza infection. J. Immunol. 2002. 168: 37773785.
  • 52
    Halstead, E. S., Mueller, Y. M., Altman, J. D. and Katsikis, P. D., In vivo stimulation of CD137 broadens primary antiviral CD8+ T-cell responses. Nat. Immunol. 2002. 3: 536541.
  • 53
    Liu, Y., Wenger, R. H., Zhao, M. and Nielsen, P. J., Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes. J. Exp. Med. 1997. 185: 251262.
  • 54
    Tan, J. T., Whitmire, J. K., Ahmed, R., Pearson, T. C. and Larsen, C. P., 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T-cell responses. J. Immunol. 1999. 163: 48594868.
  • 55
    Zimmermann, C., Seiler, P., Lane, P. and Zinkernagel, R. M., Antiviral immune responses in CTLA4 transgenic mice. J. Virol. 1997. 71: 18021807.
  • 56
    Eck, S. C. and Turka, L. A., Generation of protective immunity against an immunogenic carcinoma requires CD40/CD40L and B7/CD28 interactions but not CD4(+) T cells. Cancer Immunol. Immunother. 1999. 48: 336341.
  • 57
    Zhan, Y., Corbett, A. J., Brady, J. L., Sutherland, R. M. and Lew, A. M., CD4 help-independent induction of cytotoxic CD8 cells to allogeneic P815 tumor cells is absolutely dependent on costimulation. J. Immunol. 2000. 165: 36123619.
  • 58
    Hernandez, M. G., Shen, L. and Rock, K. L., CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T-cell responses in the absence of CD4+ T-cell help. J. Immunol. 2007. 178: 28442852.
  • 59
    Williams, J. A., Hathcock, K. S., Klug, D., Harada, Y., Choudhury, B., Allison, J. P., Abe, R. et al., Regulated costimulation in the thymus is critical for T-cell development: dysregulated CD28 costimulation can bypass the pre-TCR checkpoint. J. Immunol. 2005. 175: 41994207.
  • 60
    Vacchio, M. S., Williams, J. A. and Hodes, R. J., A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection. Eur. J. Immunol. 2005. 35: 418427.
  • 61
    Gao, J. X., Zhang, H., Bai, X. F., Wen, J., Zheng, X., Liu, J., Zheng, P. et al., Perinatal blockade of b7-1 and b7-2 inhibits clonal deletion of highly pathogenic autoreactive T cells. J. Exp. Med. 2002. 195: 959971.
  • 62
    Zhan, Y., Purton, J. F., Godfrey, D. I., Cole, T. J., Heath, W. R. and Lew, A. M., Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation. Proc. Natl. Acad. Sci. USA 2003. 100: 11971202.
  • 63
    Le Gros, G. S., Prestidge, R. L. and Watson, J. D., In-vivo modulation of thymus-derived lymphocytes with monoclonal antibodies in mice. I. Effect of anti-Thy-1 antibody on the tissue distribution of lymphocytes. Immunology 1983. 50: 537546.
  • 64
    Ghobrial, R. R., Boublik, M., Winn, H. J. and Auchincloss, H., Jr., In vivo use of monoclonal antibodies against murine T-cell antigens. Clin. Immunol. Immunopathol. 1989. 52: 486506.
  • 65
    Eichelberger, M., Allan, W., Zijlstra, M., Jaenisch, R. and Doherty, P. C., Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J. Exp. Med. 1991. 174: 875880.
  • 66
    Lee, B. O., Rangel-Moreno, J., Moyron-Quiroz, J. E., Hartson, L., Makris, M., Sprague, F., Lund, F. E. et al., CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J. Immunol. 2005. 175: 58275838.
  • 67
    Dustin, M. L. and Shaw, A. S., Costimulation: building an immunological synapse. Science 1999. 283: 649650.
  • 68
    Tuosto, L. and Acuto, O., CD28 affects the earliest signaling events generated by TCR engagement. Eur. J. Immunol. 1998. 28: 21312142.
  • 69
    Gett, A. V. and Hodgkin, P. D., A cellular calculus for signal integration by T cells. Nat. Immunol. 2000. 1: 239244.
  • 70
    Boise, L. H., Minn, A. J., Noel, P. J., June, C. H., Accavitti, M. A., Lindsten, T. and Thompson, C. B., CD28 costimulation can promote T-cell survival by enhancing the expression of Bcl-XL. Immunity 1995. 3: 8798.
  • 71
    Fraser, J. D., Irving, B. A., Crabtree, G. R. and Weiss, A., Regulation of interleukin-2 gene enhancer activity by the T-cell accessory molecule CD28. Science 1991. 251: 313316.
  • 72
    Rajasekaran, K., Xiong, V., Fong, L., Gorski, J. and Malarkannan, S., Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells. PLoS One 2010. 5. e12635
  • 73
    Dolfi, D. V., Duttagupta, P. A., Boesteanu, A. C., Mueller, Y. M., Oliai, C. H., Borowski, A. B. and Katsikis, P. D., Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T-cell responses during the effector phase in vivo. J. Immunol. 2011. 186: 45994608.
  • 74
    Borowski, A. B., Boesteanu, A. C., Mueller, Y. M., Carafides, C., Topham, D. J., Altman, J. D. et al., Memory CD8+ T cells require CD28 costimulation. J. Immunol. 2007. 179: 64946503.
  • 75
    Fuse, S., Zhang, W. and Usherwood, E. J., Control of memory CD8+ T-cell differentiation by CD80/CD86-CD28 costimulation and restoration by IL-2 during the recall response. J. Immunol. 2008. 180: 11481157.
  • 76
    Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. and Melief, C. J., T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998. 393: 480483.
  • 77
    Sutherland, R. M., Brady, J. L., Georgiou, H. M., Thomas, H. E. and Lew, A. M., Protective effect of CTLA4Ig secreted by transgenic fetal pancreas allografts. Transplantation 2000. 69: 18061812.
  • 78
    Oracki, S. A., Tsantikos, E., Quilici, C., Light, A., Schmidt, T., Lew, A. M., Martin, J. E. et al., CTLA4Ig alters the course of autoimmune disease development in Lyn−/− mice. J. Immunol. 2010. 184: 757763.
  • 79
    Borriello, F., Sethna, M. P., Boyd, S. D., Schweitzer, A. N., Tivol, E. A., Jacoby, D., Strom, T. B. et al., B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 1997. 6: 303313.
  • 80
    Jenkins, M. R., Webby, R., Doherty, P. C. and Turner, S. J., Addition of a prominent epitope affects influenza A virus-specific CD8+ T-cell immunodominance hierarchies when antigen is limiting. J. Immunol. 2006. 177: 29172925.
  • 81
    Tannock, G. A., Paul, J. A. and Barry, R. D., Relative immunogenicity of the cold-adapted influenza virus A/Ann Arbor/6/60 (A/AA/6/60-ca), recombinants of A/AA/6/60-ca, and parental strains with similar surface antigens. Infect. Immun. 1984. 43: 457462.
  • 82
    Deliyannis, G., Boyle, J. S., Brady, J. L., Brown, L. E. and Lew, A. M., A fusion DNA vaccine that targets antigen-presenting cells increases protection from viral challenge. Proc. Natl. Acad. Sci. USA 2000. 97: 66766680.
  • 83
    Belz, G. T., Xie, W., Altman, J. D. and Doherty, P. C., A previously unrecognized H-2D(b)-restricted peptide prominent in the primary influenza A virus-specific CD8(+) T-cell response is much less apparent following secondary challenge. J. Virol. 2000. 74: 34863493.
  • 84
    Vremec, D. and Shortman, K., The isolation and identification of murine dendritic cell populations from lymphoid tissues and their production in culture. Methods Mol. Biol. 2008. 415: 163178.