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Tuberculosis-Associated Immune Restoration Syndrome in HIV-1-Infected Patients Involves Tuberculin-Specific CD4 Th1 Cells and KIR-Negative T Cells¹

Anne Bourgarit^*,, Guislaine Carcelain^*, Assia Samri^*, Christophe Parizot^*, Matthieu Lafaurie, Sophie Abgrall, Veronique Delcey^¶, Eric Vicaut^||, Daniel Sereni, Brigitte Autran^2,* the PARADOX Study Group

^* Laboratory of Cellular Immunology, INSERM, Pitie-Salpetriere Hospital, Assistance Publique des Hôpitaux de Paris (APHP), Université Pierre et Marie Curie, Paris, France; Department of Internal Medicine, and Department of Infectious Diseases, Saint-Louis Hospital, APHP, Université Denis-Diderot Paris, France; Department of Infectious Diseases, Avicenne Hospital, APHP, Bobigny, France; and ^¶ Internal Medicine, ^|| Lariboisiere Hospital, Clinical Research Unit, Fernand Widal Hospital, APHP, Paris, France

Tuberculosis (TB)-associated immune restoration syndrome (IRS) is a frequent event (10 to 30%) in HIV-1-infected patients receiving antiretroviral treatment and is associated with an increased number of IFN--producing tuberculin-specific cells. To further understand the immune mechanisms of TB-IRS and to identify predictive factors, we prospectively analyzed the Th1 and TCR T cells known to be involved in mycobacterial defenses and dendritic cells at baseline and after antiretroviral and TB treatment in 24 HIV-1⁺ patients, 11 with and 13 without IRS. At baseline, these two groups differed by significantly lower proportions of TCR and V2⁺ T cells displaying the inhibitory receptors CD94/NKG2 and CD158ah,b in IRS patients. The two groups did not differ in the baseline characteristics of CD8 or CD4 T cells or TLR-2 expression on monocytes or myeloid/plasmacytoid dendritic cells. During IRS, the increase in tuberculin-specific IFN--producing cells involved only highly activated effector memory multifunctional (IFN-⁺TNF-⁺IL-2^–) CD4 T cells, whereas activated HLA-DR⁺ CD4⁺ T cells also increased during IRS. In contrast, dendritic cells decreased significantly during IRS and there were no changes in TLR-2 expression. Finally, the V2⁺ T cells, mostly killer Ig-related receptor (KIR) (CD94/NKG2^– and CD158^–), significantly peaked during IRS but not in non-IRS patients. In conclusion, IRS is associated with an increase in the number of activated tuberculin-specific effector memory CD4 T cells and of KIR^–V2⁺ TCR⁺ T cells. Higher proportions of V2⁺TCR⁺ T cells lacking KIR expression are present as baseline and distinguish patients who will develop IRS from those who will not.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Agence Nationale pour la Recherche sur le Sida et les hépatites virales. A.B. was a SIDACTION fellow.

² Address correspondence and reprint requests to Dr. Brigitte Autran, Cellular and Tissular Immunology Laboratory, Hôpital Pitie-Salpetriere, Batiment CERVI, 47-83, Boulevard de l’Hopital, 75013 Paris, France. E-mail address: brigitte.autran{at}psl.aphp.fr

³ Abbreviations used in this paper: IRS, immune restoration syndrome; DC, dendritic cell; HAART, highly active antiretroviral therapy; IQR, interquartile range; KIR, killer Ig-related receptor; mDC, myeloid DC; MFI, mean fluorescence intensity; Mtb, Mycobacterium tuberculosis; pDC, plasmacytoid DC; PPD, purified protein derivative; SFC, spot-forming cell; TB, tuberculosis.