Downregulation of CD94/NKG2A inhibitory receptors on CD8+T cells in HIV infection is more pronounced in subjects with detected viral load than in their aviraemic counterparts
© Zeddou et al; licensee BioMed Central Ltd. 2007
Received: 02 April 2007
Accepted: 10 October 2007
Published: 10 October 2007
The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated CD8+ T lymphocytes. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In this study, CD94/NKG2A receptor expression on CD8+ T lymphocytes and NK cells was assessed in 46 HIV-1-infected patients (24 viraemic, 22 aviraemic) and 10 healthy volunteers. The percentage of CD8+ T lymphocytes expressing the CD94/NKG2A inhibitory heterodimer was very significantly decreased in HIV-1-infected patients in comparison with non-infected controls. Within the HIV infected patients, the proportion of CD8+ T lymphocytes and NK cells expressing CD94/NKG2A was higher in subjects with undetectable viral loads in comparison with their viraemic counterparts. No significant difference was detected in the proportion of CD8+ T lymphocytes expressing the activatory CD94/NKG2C heterodimer between the HIV-1 infected patients and the healthy donors, nor between the vireamic and avireamic HIV-1 infected patients. In conclusion, chronic stimulation with HIV antigens in viraemic patients leads to a decreased rather than increased CD94/NKG2A expression on CD8+ T lymphocytes and NK cells.
The CD94/NKG2 heterodimer is a C-type lectin receptor, formed by the covalent association of CD94, a protein with a short non-signaling intracytoplasmic tail , and one of the NKG2 molecules. To generate a functional receptor, CD94 is disulfide linked with a member of the NKG2 family, namely NKG2A, -B, -C or -E [2, 3]. In humans, CD94/NKG2A interacts with complexes of non-classical HLA-E molecules [4, 5]. The intracellular domain of NKG2A contains immunoreceptor tyrosine-based inhibition motifs (ITIMs), responsible for transducing inhibitory signals . The other NKG2 members lack ITIMs and are linked to transmembrane proteins, such as DAP10 and DAP12 which contain immunoreceptor tyrosine-based activating motifs and transduce activating signals . CD94/NKG2A is normally expressed on most NK cells and on a small fraction of CD8+ T lymphocytes. The proportion of NK cells bearing the CD94/NKG2A inhibitory receptor decreases in advanced HIV infection , in contrast with other inhibitory receptors of the KIR family which are upregulated. It is presently unknown if HIV infection has similar effects on the expression of the CD94/NKG2A inhibitory receptor by CD8+ T cells. A few studies have shown that CD94 expression by CD8+ T cells is increased during HIV infection [9–11] and have led to postulate that increased expression of the CD94/NKG2A inhibitory receptors is one of the mechanisms rendering HIV-specific CD8+ T lymphocytes unable to control HIV-1 infection . Nevertheless, the simultaneous expression of both subunits of the inhibitory receptor on CD8+ T cells has hardly been studied in HIV infection. Costa et al. using two-color FACS analysis to study CD3+ NKG2A+ T cells, showed no difference between uninfected controls, long term non progressors or aviraemic subjects under HAART. A slight increase was noted in subjects with active viral replication , in contradiction with the downregulation previously observed on NK cells from infected subjects.
In HIV infected patients, there was a weak but significant correlation between the proportion of CD8+ T lymphocytes and NK cells expressing the CD94/NKG2A heterodimer (r2 = 0,09184; p = 0.0406) and the proportion of NK cells expressing the inhibitory receptor tended to be lower in viraemic patients than in subjects with less than 50 copies/ml. (mean ± SEM, 43.11 ± 5.67% vs. 56.05 ± 4.67%; p = 0.019). There was no correlation of the expression of the inhibitory receptor with absolute or relative CD4 counts (data not shown).
In summary, we observed a downregulation of CD94/NKG2A on CD8+ T cells in HIV infection, in accordance with what was previously described for NK cells. The mechanisms linking viral replication with downregulation of the inhibitory CD94/NKG2A receptor remains obscure. Upregulation of CD94/NKG2A has previously been observed in various animal models of viral and bacterial infections  and in chronic antigenic stimulation . Loss of CD94/NKG2A might correspond to the terminal differentiation which occurs in a large fraction of CD8+ T cells during HIV infection. Indeed, recent observations made in an experimental model of persistent polyoma virus infections suggest that CD94/NKG2A CD8+ T lymphocytes might constitute a less differentiated subset of CD8+ T cells and maintain a higher proliferative potential and capacity to secrete IL-2 . Whatever is the mechanism involved, the loss of CD94/NKG2A in HIV infection could also contribute to the polyclonal activation which characterizes HIV infection.
This work was supported by the Fond National de la Recherche Scientifique (FNRS), the Centre anticancéreux près l'Université de Liège (CAC) and a grant from the Walloon Region.
- Chang CA, Rodriguez M, Carretero M, Lopez-Botet JH, Phillips , Lanier LL: Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. Eur J Immunol. 1995, 25: 2433-2437. 10.1002/eji.1830250904.View ArticlePubMedGoogle Scholar
- Brooks AG, Posch PE, Scorzelli CJ, Borrego F, Coligan JE: NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J Exp Med. 1997, 185: 795-800. 10.1084/jem.185.4.795.PubMed CentralView ArticlePubMedGoogle Scholar
- Carretero M, Cantoni C, Bellon T, Bottino C, Biassoni R, Rodriguez A, Perez-Villar JJ, Moretta L, Moretta A, Lopez-Botet M: The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. Eur J Immunol. 1997, 27: 563-567. 10.1002/eji.1830270230.View ArticlePubMedGoogle Scholar
- Brooks AG, Borrego F, Posch PE, Patamawenu A, Scorzelli CJ, Ulbrecht M, Weiss EH, Coligan JE: Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J Immunol. 1999, 162 (1): 305-313.PubMedGoogle Scholar
- Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE: HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci USA. 1998, 95: 5199-5204. 10.1073/pnas.95.9.5199.PubMed CentralView ArticlePubMedGoogle Scholar
- Kabat J, Borrego F, Brooks A, Coligan JE: Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. J Immunol. 2002, 169: 1948-1958.View ArticlePubMedGoogle Scholar
- Lanier LL, Corliss B, Wu J, Phillips JH: Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity. 1998, 8: 693-701. 10.1016/S1074-7613(00)80574-9.View ArticlePubMedGoogle Scholar
- Mavilio D, Benjamin J, Daucher M, Lombardo G, Kottilil S, Planta MA, Marcenaro E, Bottino C, Moretta L, Moretta A, Fauci AS: Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc Natl Acad Sci USA. 2003, 100: 15011-15016. 10.1073/pnas.2336091100.PubMed CentralView ArticlePubMedGoogle Scholar
- Galiani MD, Aguado E, Tarazona R, Romero P, Molina I, Santamaria M, Solana R, Pena J: Expression of killer inhibitory receptors on cytotoxic cells from HIV-1-infected individuals. Clin Exp Immunol. 1999, 115: 472-476. 10.1046/j.1365-2249.1999.00833.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Tarazona R, DelaRosa O, Casado JG, Torre-Cisneros J, Villanueva JL, Galiani MD, Pena J, Solana R: NK-associated receptors on CD8 T cells from treatment-naive HIV-infected individuals: defective expression of CD56. AIDS. 2002, 16: 197-200. 10.1097/00002030-200201250-00008.View ArticlePubMedGoogle Scholar
- Wesch D, Kabelitz D: Differential expression of natural killer receptors on Vdelta1 gammadelta T cells in HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2003, 33: 420-425.View ArticlePubMedGoogle Scholar
- Moser JM, Byers AM, Lukacher AE: NK cell receptors in antiviral immunity. Curr Opin Immunol. 2002, 14: 509-516. 10.1016/S0952-7915(02)00357-6.View ArticlePubMedGoogle Scholar
- Costa P, Rusconi S, Fogli M, Mavilio D, Murdaca G, Puppo F, Mingari MC, Galli M, Moretta L, De MA: Low expression of inhibitory natural killer receptors in CD8 cytotoxic T lymphocytes in long-term non-progressor HIV-1-infected patients. AIDS. 2003, 17: 257-260. 10.1097/00002030-200301240-00017.View ArticlePubMedGoogle Scholar
- McMahon CW, Zajac AJ, Jamieson AM, Corral L, Hammer GE, Ahmed R, Raulet DH: Viral and bacterial infections induce expression of multiple NK cell receptors in responding CD8(+) T cells. J Immunol. 2002, 169: 1444-1452.View ArticlePubMedGoogle Scholar
- Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones SL, Blum HE, Pircher H: Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol. 2005, 79: 12112-12116. 10.1128/JVI.79.18.12112-12116.2005.PubMed CentralView ArticlePubMedGoogle Scholar
- Byers AM, Andrews NP, Lukacher AE: CD94/NKG2A expression is associated with proliferative potential of CD8 T cells during persistent polyoma virus infection. J Immunol. 2006, 176: 6121-6129.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.