Share This Article:

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

Abstract Full-Text HTML XML Download Download as PDF (Size:4154KB) PP. 83-95
DOI: 10.4236/oji.2014.43012    2,643 Downloads   3,203 Views  

ABSTRACT

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.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

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.

References

[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.
http://dx.doi.org/10.1038/44385
[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.
http://dx.doi.org/10.1038/35065118
[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.
http://dx.doi.org/10.1146/annurev-immunol-032712-095954
[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.
http://dx.doi.org/10.1038/nm.1972
[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. http://dx.doi.org/10.1016/j.immuni.2011.04.020
[6] Badovinac, V.P. and Harty, J.T. (2006) Programming, Demarcating, and Manipulating CD8+ T-Cell Memory. Immunological Reviews, 211, 67-80.
http://dx.doi.org/10.1111/j.0105-2896.2006.00384.x
[7] Appay, V., Douek, D.C. and Price, D.A. (2008) CD8+ T Cell Efficacy in Vaccination and Disease. Nature Medicine, 14, 623-628.
http://dx.doi.org/10.1038/nm.f.1774
[8] Harty, J. and Badovinac, V. (2008) Shaping and Reshaping CD8+ T-Cell Memory. Nature Reviews Immunology, 8, 107-119.
http://dx.doi.org/10.1038/nri2251
[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.
http://dx.doi.org/10.4049/jimmunol.169.2.638
[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.
http://dx.doi.org/10.4049/jimmunol.170.5.2461
[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.
http://dx.doi.org/10.4049/jimmunol.168.1.29
[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.
http://dx.doi.org/10.1182/blood-2005-11-007237
[13] Ahmed, R., Bevan, M., Reiner, S. and Fearon, D. (2009) The Precursors of Memory: Models and Controversies. Nature Reviews Immunology, 9, 662-668.
http://dx.doi.org/10.1038/nri2619
[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.
http://dx.doi.org/10.1182/blood-2005-12-4818
[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.
http://dx.doi.org/10.1097/QAD.0b013e3283377a1e
[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.
http://dx.doi.org/10.1128/JVI.00138-10
[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.
http://dx.doi.org/10.1111/imr.12069
[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.
http://dx.doi.org/10.4049/jimmunol.165.2.1082
[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.
http://dx.doi.org/10.4049/jimmunol.177.10.7406
[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.
http://dx.doi.org/10.1128/JVI.01754-06
[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.
http://dx.doi.org/10.1016/S0140-6736(95)12269-2
[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.
http://dx.doi.org/10.1093/infdis/171.3.686
[24] Roederer, M. and Koup, R.A. (2003) Optimized Determination of T Cell Epitope Responses. Journal of Immunological Methods, 274, 221-228.
http://dx.doi.org/10.1016/S0022-1759(02)00423-4
[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.
http://dx.doi.org/10.1097/00002030-200209060-00015
[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.
http://dx.doi.org/10.1128/JVI.02742-06
[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.
http://dx.doi.org/10.4049/jimmunol.177.7.4330
[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.
http://dx.doi.org/10.1128/JVI.01707-10
[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.
http://dx.doi.org/10.1038/nm0402-379
[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.
http://dx.doi.org/10.1016/S1471-4906(02)02326-8
[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.
http://dx.doi.org/10.1038/nm0702-673
[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.
http://dx.doi.org/10.1111/j.1365-2567.2007.02589.x
[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.
http://dx.doi.org/10.4049/jimmunol.0803801
[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.
http://dx.doi.org/10.1086/649430
[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.
http://dx.doi.org/10.1038/nri2274
[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.
http://dx.doi.org/10.1371/journal.pmed.0050100
[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.
http://dx.doi.org/10.1002/eji.200737768
[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.
http://dx.doi.org/10.1016/j.tim.2008.08.011
[42] Klenerman, P. and Hill, A. (2005) T Cells and Viral Persistence: Lessons from Diverse Infections. Nature Immunology, 6, 873-879.
http://dx.doi.org/10.1038/ni1241
[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.
http://dx.doi.org/10.1084/jem.20060995
[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.
http://dx.doi.org/10.1128/JVI.79.20.12952-12960.2005
[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.
http://dx.doi.org/10.1084/jem.193.2.181
[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.
http://dx.doi.org/10.1128/JVI.00182-09
[47] Shin, H. and Wherry, E. (2007) CD8 T Cell Dysfunction during Chronic Viral Infection. Current Opinion in Immunology, 19, 408-415.
http://dx.doi.org/10.1016/j.coi.2007.06.004
[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.
http://dx.doi.org/10.1128/JVI.77.8.4911-4927.2003
[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.
http://dx.doi.org/10.1084/jem.20070322
[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.
http://dx.doi.org/10.1038/nature05115
[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.
http://dx.doi.org/10.1084/jem.20081398
[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.
http://dx.doi.org/10.1038/nm1482
[54] Brenchley, J.M. (2002) Expression of CD57 Defines Replicative Senescence and Antigen-Induced Apoptotic Death of CD8+ T Cells. Blood, 101, 2711-2720.
http://dx.doi.org/10.1182/blood-2002-07-2103
[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.
http://dx.doi.org/10.1016/S0092-8674(02)01139-X
[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.
http://dx.doi.org/10.1038/ni.1679

  
comments powered by Disqus

Copyright © 2018 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.