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Memory Phenotypes of HIV-Specific CD8+ T Cell Responses Are Independent of Functional Activity as Defined by Cytokine Output

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DOI: 10.4236/oji.2014.43012    2,643 Downloads   3,203 Views  


Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27-CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27-CD45RA-(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.

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The authors declare no conflicts of interest.

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Richmond, M. , Kiazyk, S. , McKinnon, L. , Nyanga, B. , Wachihi, C. , Kimani, M. , Kimani, J. , Plummer, F. and Blake Ball, T. (2014) Memory Phenotypes of HIV-Specific CD8+ T Cell Responses Are Independent of Functional Activity as Defined by Cytokine Output. Open Journal of Immunology, 4, 83-95. doi: 10.4236/oji.2014.43012.


[1] Sallusto, F., Lenig, D., Forster, R., Lipp, M. and Lanzavecchia, A. (1999) Two Subsets of Memory T Lymphocytes with Distinct Homing Potentials and Effector Functions. Nature, 401, 708-712.
[2] Champagne, P., Ogg, G., King, A., Knabenhans, C., Ellefsen, K., Nobile, M., et al. (2001) Skewed Maturation of Memory HIV-Specific CD8 T Lymphocytes. Nature, 410, 106-111.
[3] Mueller, S.N., Gebhardt, T., Carbone, F.R. and Heath, W.R. (2012) Memory T Cell Subsets, Migration Patterns, and Tissue Residence. Annual Review of Immunology, 31, 137-161.
[4] Chomont, N., El-Far, M., Ancuta, P., Trautmann, L., Procopio, F., Yassine-Diab, B., et al. (2009) HIV Reservoir Size and Persistence Are Driven by T Cell Survival and Homeostatic Proliferation. Nature Medicine, 15, 893-900.
[5] van Gisbergen, K.P.J.M., Klarenbeek, P.L., Kragten, N.A.M., Unger, P.-P.A., Nieuwenhuis, M.B.B., Wensveen, F.M., et al. (2011) The Costimulatory Molecule CD27 Maintains Clonally Diverse CD8(+) T Cell Responses of Low Antigen Affinity to Protect against Viral Variants. Immunity, 35, 97-108.
[6] Badovinac, V.P. and Harty, J.T. (2006) Programming, Demarcating, and Manipulating CD8+ T-Cell Memory. Immunological Reviews, 211, 67-80.
[7] Appay, V., Douek, D.C. and Price, D.A. (2008) CD8+ T Cell Efficacy in Vaccination and Disease. Nature Medicine, 14, 623-628.
[8] Harty, J. and Badovinac, V. (2008) Shaping and Reshaping CD8+ T-Cell Memory. Nature Reviews Immunology, 8, 107-119.
[9] Unsoeld, H., Krautwald, S., Voehringer, D., Kunzendorf, U. and Pircher, H. (2002) Cutting Edge: CCR7+ and CCR7- Memory T Cells Do Not Differ in Immediate Effector Cell Function. The Journal of Immunology, 169, 638-641.
[10] Ravkov, E.V., Myrick, C.M. and Altman, J.D. (2003) Immediate Early Effector Functions of Virus-Specific CD8+CCR7+ Memory Cells in Humans Defined by HLA and CC Chemokine Ligand 19 Tetramers. The Journal of Immunology, 170, 2461-2468.
[11] Pitcher, C., Hagen, S., Walker, J., Lum, R., Mitchell, B., Maino, V., et al. (2002) Development and Homeostasis of T Cell Memory in Rhesus macaque. The Journal of Immunology, 168, 29-43.
[12] Carrasco, J., Godelaine, D., Van Pel, A., Boon, T. and van der Bruggen, P. (2006) CD45RA on Human CD8 T Cells Is Sensitive to the Time Elapsed since the Last Antigenic Stimulation. Blood, 108, 2897-2905.
[13] Ahmed, R., Bevan, M., Reiner, S. and Fearon, D. (2009) The Precursors of Memory: Models and Controversies. Nature Reviews Immunology, 9, 662-668.
[14] Betts, M.R., Nason, M., West, S., De Rosa S., Migueles, S., Abraham J., et al. (2006) HIV Nonprogressors Preferentially Maintain Highly Functional HIV-Specific CD8+ T Cells. Blood, 107, 4781-4789.
[15] Owen, R.E., Heitman, J.W., Hirschkorn, D.F., Lanteri, M.C., Biswas, H.H., Martin, J.N., et al. (2010) HIV+ Elite Controllers Have Low HIV-Specific T-Cell Activation yet Maintain Strong, Polyfunctional T-Cell Responses. AIDS, 24, 1095-1105.
[16] Freel, S.A., Lamoreaux, L., Chattopadhyay, P.K., Saunders, K., Zarkowsky, D., Overman, R.G., et al. (2010) Phenotypic and Functional Profile of HIV-Inhibitory CD8 T Cells Elicited by Natural Infection and Heterologous Prime/ Boost Vaccination. Journal of Virology, 84, 4998-5006.
[17] Demers, K.R., Reuter, M.A. and Betts, M.R. (2013) CD8+ T-Cell Effector Function and Transcriptional Regulation during HIV Pathogenesis. Immunological Reviews, 254, 190-206.
[18] Gea-Banacloche, J.C., Migueles, S.A., Martino, L., Shupert, W.L., McNeil, A.C., Sabbaghian, M.S., et al. (2000) Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors. The Journal of Immunology, 165, 1082-1092.
[19] Horton, H., Frank, I., Baydo, R., Jalbert, E., Penn, J., Wilson, S., et al. (2006) Preservation of T Cell Proliferation Restricted by Protective HLA Alleles Is Critical for Immune Control of HIV-1 Infection. The Journal of Immunology, 177, 7406-7415.
[20] Day, C.L., Kiepiela, P., Leslie, A.J., Van Der Stok, M., Nair, K., Ismail, N., et al. (2007) Proliferative Capacity of Epitope-Specific CD8 T-Cell Responses Is Inversely Related to Viral Load in Chronic Human Immunodeficiency Virus Type 1 Infection. Journal of Virology, 81, 434-438.
[21] Migueles, S.A., Laborico, A.C., Shupert, W.L., Sabbaghian, M.S., Rabin, R., Hallahan, C.W., et al. (2002) HIV-Specific CD8+ T Cell Proliferation Is Coupled to Perforin Expression and Is Maintained in Nonprogressors. Nature Immunology, 3, 1061-1068.
[22] Fowke, K.R., Nagelkerke, N.J., Kimani, J., Simonsen, J.N., Anzala, A.O., Bwayo, J.J., et al. (1996) Resistance to HIV-1 Infection among Persistently Seronegative Prostitutes in Nairobi, Kenya. The Lancet, 348, 1347-1351.
[23] Anzala, O.A., Nagelkerke, N.J., Bwayo, J.J., Holton, D., Moses, S., Ngugi, E.N., et al. (1995) Rapid Progression to Disease in African Sex Workers with Human Immunodeficiency Virus Type 1 Infection. The Journal of Infectious Diseases, 171, 686-689.
[24] Roederer, M. and Koup, R.A. (2003) Optimized Determination of T Cell Epitope Responses. Journal of Immunological Methods, 274, 221-228.
[25] Dowling, W., Kim, B., Mason, C., Wasunna, K., Alam, U., Elson, L., et al. (2002) Forty-One Near Full-Length HIV-1 Sequences from Kenya Reveal an Epidemic of Subtype A and A-Containing Recombinants. AIDS, 16, 1809-1820.
[26] Neilson, J.R., John, G.C., Carr, J.K., Lewis, P., Kreiss, J.K., Jackson, S., et al. (1999) Subtypes of Human Immunodeficiency Virus Type 1 and Disease Stage among Women in Nairobi, Kenya. Journal of Virology, 73, 4393-4403.
[27] Peters, H.O., Mendoza, M.G., Capina, R.E., Luo, M., Mao, X., Gubbins, M., et al. (2008) An Integrative Bioinformatic Approach for Studying Escape Mutations in Human Immunodeficiency Virus Type 1 Gag in the Pumwani Sex Worker Cohort. Journal of Virology, 82, 1980-1992.
[28] Takata, H. and Takiguchi, M., (2006) Three Memory Subsets of Human CD8+ T Cells Differently Expressing Three Cytolytic Effector Molecules. The Journal of Immunology, 177, 4330-4340.
[29] Richmond, M., Mckinnon, L.R., Kiazyk, S.A.K., Wachihi, C., Kimani, M., Kimani, J., et al. (2011) Epitope Mapping of HIV-Specific CD8+ T Cell Responses by Multiple Immunological Readouts Reveals Distinct Specificities Defined by Function. Journal of Virology, 85, 1275-1286.
[30] Appay, V., Dunbar, P., Callan, M., Klenerman, P., Gillespie, G., Papagno, L., et al. (2002) Memory CD8+ T Cells Vary in Differentiation Phenotype in Different Persistent Virus Infections. Nature Medicine, 8, 379-385.
[31] van Baarle, M.D., Kostense, S., van Oers, M.H.J., Hamann, D. and Miedema, F. (2002) Failing Immune Control as a Result of Impaired CD8+ T-Cell Maturation: CD27 Might Provide a Clue. Trends in Immunology, 23, 586-591.
[32] Greene, W.C. and Peterlin, B.M. (2002) Charting HIV’s Remarkable Voyage through the Cell: Basic Science as a Passport to Future Therapy. Nature Medicine, 8, 673-680.
[33] Decrion, A., Varin, A., Drobacheff, C., Estavoyer, J. and Herbein, G. (2007) A Subset of Functional Effector-Memory CD8+ T Lymphocytes in Human Immunodeficiency Virus-Infected Patients. Immunology, 121, 405-415.
[34] Stevenson, M. (2003) HIV-1 Pathogenesis. Nature Medicine, 9, 853-860.
[35] Burgers, W., Riou, C., Mlotshwa, M., Maenetje, P., de Assis Rosa, D., Brenchley, J., et al. (2009) Association of HIV- Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point. The Journal of Immunology, 182, 4751-4761.
[36] Ganesan, A., Chattopadhyay, P., Brodie, T., Qin, J., Gu, W., Mascola, J., et al. (2010) Immunologic and Virologic Events in Early HIV Infection Predict Subsequent Rate of Progression. The Journal of Infectious Diseases, 201, 272-284.
[37] Seder, R., Darrah, P. and Roederer, M. (2008) T-Cell Quality in Memory and Protection: Implications for Vaccine Design. Nature Reviews Immunology, 8, 247-258.
[38] Streeck, H., Brumme, Z.L., Anastario, M., Cohen, K.W., Jolin, J.S., Meier, A., et al. (2008)Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1-Specific CD8+ T Cells. PLoS Medicine, 5, e100.
[39] Miller, J., van der Most, R., Akondy, R., Glidewell, J., Albott, S., Masopust, D., et al. (2008) Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines. Immunity, 28, 710-722.
[40] Duvall, M., Precopio, M., Ambrozak, D., Jaye, A., McMichael, A., Whittle, H., et al. (2008) Polyfunctional T Cell Responses Are a Hallmark of HIV-2 Infection. European Journal of Immunology, 38, 350-363.
[41] Kiazyk, S.A.K. and Fowke, K.R. (2008) Loss of CD127 Expression Links Immune Activation and CD4+ T Cell Loss in HIV Infection. Trends in Microbiology, 16, 567-573.
[42] Klenerman, P. and Hill, A. (2005) T Cells and Viral Persistence: Lessons from Diverse Infections. Nature Immunology, 6, 873-879.
[43] Vezys, V., Masopust, D., Kemball, C.C., Barber, D.L., O’Mara, L.A., Larsen, C.P., et al. (2006) Continuous Recruitment of Naive T Cells Contributes to Heterogeneity of Antiviral CD8 T Cells during Persistent Infection. Journal of Experimental Medicine, 203, 2263-2269.
[44] Allen, T., Yu, X., Kalife, E., Reyor, L., Lichterfeld, M., John, M., et al. (2005) De Novo Generation of Escape Variant-Specific CD8+ T-Cell Responses Following Cytotoxic T-Lymphocyte Escape in Chronic Human Immunodeficiency Virus Type 1 Infection. Journal of Virology, 79, 12952-12960.
[45] Goulder, P.J., Altfeld, M.A., Rosenberg, E.S., Nguyen, T., Tang, Y., Eldridge, R.L., et al. (2001) Substantial Differences in Specificity of HIV-Specific Cytotoxic T Cells in Acute and Chronic HIV Infection. The Journal of Experimental Medicine, 193, 181-194.
[46] Streeck, H., Jolin, J.S., Qi, Y., Yassine-Diab, B., Johnson, R.C., Kwon, D.S., et al. (2009) Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4+ T Cells. Journal of Virology, 83, 7641-7648.
[47] Shin, H. and Wherry, E. (2007) CD8 T Cell Dysfunction during Chronic Viral Infection. Current Opinion in Immunology, 19, 408-415.
[48] Wherry, E., Blattman, J., Murali-Krishna, K., van der Most, R. and Ahmed, R. (2003) Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment. Journal of Virology, 77, 4911-4927.
[49] Kristensen, N., Christensen, J. and Thomsen, A. (2002) High Numbers of IL-2-Producing CD8+ T Cells during Viral Infection: Correlation with Stable Memory Development. Journal of General Virology, 83, 2123-2133.
[50] Hikono, H., Kohlmeier, J.E., Takamura, S., Wittmer, S.T., Roberts, A.D. and Woodland, D.L. (2007) Activation Phenotype, Rather than Central- or Effector-Memory Phenotype, Predicts the Recall Efficacy of Memory CD8+ T Cells. The Journal of Experimental Medicine, 204, 1625-1636.
[51] Day, C., Kaufmann, D., Kiepiela, P., Brown, J., Moodley, E., Reddy, S., et al. (2006) PD-1 Expression on HIV-Specific T Cells Is Associated with T-Cell Exhaustion and Disease Progression. Nature, 443, 350-354.
[52] Jones, R., Ndhlovu, L., Barbour, J., Sheth, P., Jha, A., Long, B., et al. (2008) Tim-3 Expression Defines a Novel Population of Dysfunctional T Cells with Highly Elevated Frequencies in Progressive HIV-1 Infection. The Journal of Experimental Medicine, 205, 2763-2779.
[53] Trautmann, L., Janbazian, L., Chomont, N., Said, E., Gimmig, S., Bessette, B., et al. (2006) Upregulation of PD-1 Expression on HIV-Specific CD8+ T Cells Leads to Reversible Immune Dysfunction. Nature Medicine, 12, 1198-1202.
[54] Brenchley, J.M. (2002) Expression of CD57 Defines Replicative Senescence and Antigen-Induced Apoptotic Death of CD8+ T Cells. Blood, 101, 2711-2720.
[55] Kaech, S.M., Hemby, S., Kersh, E. and Ahmed, R. (2002) Molecular and Functional Profiling of Memory CD8 T Cell Differentiation. Cell, 111, 837-851.
[56] Blackburn, S., Shin, H., Haining, W., Zou, T., Workman, C., Polley, A., et al. (2009) Coregulation of CD8+ T Cell Exhaustion by Multiple Inhibitory Receptors during Chronic Viral Infection. Nature Immunology, 10, 29-37.

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