High Activation of γδ T Cells and the γδ2pos T-Cell Subset Is Associated With the Onset of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome, ANRS 12153 CAPRI NK

Abstract

Background: Human Immunodeficiency Virus 1 (HIV-1) and Mycobacterium Tuberculosis (Mtb) co-infected patients are commonly at risk of immune reconstitution inflammatory syndrome (IRIS) when initiating antiretroviral treatment (ART). Evidence indicates that innate immunity plays a role in TB-IRIS. Here, we evaluate the phenotype of Gamma-delta (γδ) T cells and invariant Natural Killer (iNK) T cells in tuberculosis-associated IRIS. Methods: Forty-eight HIV+/TB+ patients (21 IRIS) and three control groups: HIV-/TB- (HD, n = 11), HIV+/TB- (n = 26), and HIV-/TB+ (n = 22) were studied. Samples were taken at ART initiation (week 2 of anti-tuberculosis treatment) and at the diagnosis of IRIS for HIV+/TB+; before ART for HIV+/TB-, and at week 2 of anti-tuberculosis treatment for HIV-/TB+ patients. γδ T cells and Invariant natural killer T (iNKT) cells were analyzed by flow cytometry. Results: Before ART, IRIS, and non-IRIS patients showed a similar proportion of γδ^pos T and iNKT cells. HLA-DR on γδ^pos T cells and δ2^posγδ^pos T cells was significantly higher in TB-IRIS vs. non-IRIS patients and controls (p < 0.0001). NKG2D expression on γδ^pos T cells and the δ2^posγδ^pos T cell subset was lower in HIV+/TB+ patients than controls. CD158a expression on γδ^pos T cells was higher in TB-IRIS than non-IRIS (p = 0.02), HIV+/TB-, and HIV-/TB- patients. Conclusion: The higher activation of γδ^posT cells and the γδ2^posγδ^pos T cell subset suggests that γδ T cells may play a role in the pathogenesis of TB-IRIS.

Keywords: HIV; gamma delta T cells; immune reconstitution inflammatory syndrome; invariant NKT cells; tuberculosis.

Figure 1

δ2^posγδ^posT cells and the ratio of δ2^posγδ^pos: δ2^negγδ^posT cell in TB-IRIS, and non-IRIS at baseline. The proportion of δ2^posγδ^pos T cell (A), the ratio of δ2^posγδ^pos: δ2^negγδ^pos T cell (B) in TB-IRIS, non-IRIS, and control groups: [TB (TB+/HIV–), HIV (HIV+/TB–), HD (HIV–/TB–)] are shown. Results are expressed as median and 25–75% interquartile range. Significant p-values (p < 0.05) are indicated.

Figure 2

HLA-DR expression on δ2^posγδ^pos T cell, and total lymphocytes in TB-IRIS, and non-IRIS at baseline. The proportion of HLA-DR^posδ2^posγδ^pos T cell (A), HLA-DR^pos on total lymphocytes (B) in TB-IRIS, non-IRIS, and control groups [TB (TB+/HIV–), HIV (HIV+/TB–), HD (HIV–/TB–)] are shown. The results are median and 25–75% interquartile range. Significant p-values (p < 0.05) are indicated.

Figure 3

NKG2D, and NKG2C expression on δ2^posγδ^pos T cell in TB-IRIS and non-IRIS at baseline. The proportion of NKG2D^posδ2^posγδ^pos T cell (A), NKG2C^posδ2^posγδ^pos T cell (B) in TB-IRIS, non-IRIS, and control groups [TB (TB+/HIV–), HIV (HIV+/TB–), and HD (HIV–/TB–)] are shown. The results are median and 25–75% interquartile range. Significant p-values (p < 0.05) are denoted.

Figure 4

Killer Immunoglobulin-like receptors CD158a, and CD158b expression on δ2^posγδ^pos T cell subset in TB-IRIS and non-IRIS at baseline. The proportion of CD158a^posδ2^posγδ^pos T cell (A), CD158b^posδ2^posγδ^pos T cell (B) in TB-IRIS, non-IRIS, and control groups [TB (TB+/HIV–), HIV (HIV+/TB–), and HD (HIV–/TB–)] are shown. The results are median and 25–75% interquartile range. Significant p-values (p < 0.05) are denoted.

Figure 5

The phenotype of circulating invariant NKT cells and CD56⁺NKT cell subset in TB-IRIS and non-IRIS at baseline. The proportion of circulating Vα24Jα18⁺ iNKT cells (A), or CD56⁺Vα24Jα18⁺ iNKT cells among total CD3⁺ T cells (B); and proportion of CD8⁺ iNKT cells among total Vα24Jα18⁺ iNKT cells (C) or CD8⁺CD56⁺iNKT cells among Vα24Jα18⁺CD56⁺ (D), in TB-IRIS, non-IRIS, and control groups [TB (TB+/HIV–), HIV (HIV+/TB–), and HD (HIV–/TB–)] are shown. The results are shown as median and 25–75% interquartile range. Significant p-values (p < 0.05) are indicated.

Figure 6

CD69, and CD161 expression on iNKT cells and CD56⁺iNKT cell subset in TB-IRIS and non-IRIS at baseline. The proportion of CD69 expression on CD3⁺Vα24Jα18⁺ iNKT cells (A), and on CD56⁺CD3⁺Vα24Jα18⁺ (B); the proportion of CD161 expression on Vα24Jα18⁺ iNKT cells (C), and on CD56⁺CD3⁺Vα24Jα18⁺ iNKT cells (D) in TB-IRIS, non-IRIS, and control groups [TB (HIV–/TB+), HIV (HIV+/TB–), and HD (HIV–/TB–)] are shown. The results are median and 25–75% interquartile range. Significant p-values (p < 0.05) are presented.