Lymph node CXCR5+ NK cells associate with control of chronic SHIV infection
Sheikh Abdul Rahman, James M. Billingsley, Ashish Arunkumar Sharma, Tiffany M. Styles, Sakthivel Govindaraj, Uma Shanmugasundaram, Hemalatha Babu, Susan Pereira Riberio, Syed A. Ali, Gregory K. Tharp, Chris Ibegbu, Stephen N. Waggoner, R. Paul Johnson, Rafick-Pierre Sekaly, Francois Villinger, Steve E. Bosinger, Rama Rao Amara, Vijayakumar Velu
Sheikh Abdul Rahman, James M. Billingsley, Ashish Arunkumar Sharma, Tiffany M. Styles, Sakthivel Govindaraj, Uma Shanmugasundaram, Hemalatha Babu, Susan Pereira Riberio, Syed A. Ali, Gregory K. Tharp, Chris Ibegbu, Stephen N. Waggoner, R. Paul Johnson, Rafick-Pierre Sekaly, Francois Villinger, Steve E. Bosinger, Rama Rao Amara, Vijayakumar Velu
View: Text | PDF
Research Article AIDS/HIV Immunology

Lymph node CXCR5+ NK cells associate with control of chronic SHIV infection

Abstract

The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to an HIV/SIV cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCFs) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of NK cells in macaque lymph nodes that expressed BCF-homing receptor CXCR5 and accumulated within BCFs during chronic SHIV infection. These CXCR5+ follicular NK cells exhibited an activated phenotype coupled with heightened effector functions and a unique transcriptome characterized by elevated expression of cytolytic mediators (e.g., perforin and granzymes, LAMP-1). CXCR5+ NK cells exhibited high expression of FcγRIIa and FcγRIIIa, suggesting a potential for elevated antibody-dependent effector functionality. Consistently, accumulation of CXCR5+ NK cells showed a strong inverse association with plasma viral load and the frequency of germinal center follicular Th cells that comprise a significant fraction of the viral reservoir. Moreover, CXCR5+ NK cells showed increased expression of transcripts associated with IL-12 and IL-15 signaling compared with the CXCR5– subset. Indeed, in vitro treatment with IL-12 and IL-15 enhanced the proliferation of CXCR5+ granzyme B+ NK cells. Our findings suggest that follicular homing NK cells might be important in immune control of chronic SHIV infection, and this may have important implications for HIV cure strategies.

Authors

Sheikh Abdul Rahman, James M. Billingsley, Ashish Arunkumar Sharma, Tiffany M. Styles, Sakthivel Govindaraj, Uma Shanmugasundaram, Hemalatha Babu, Susan Pereira Riberio, Syed A. Ali, Gregory K. Tharp, Chris Ibegbu, Stephen N. Waggoner, R. Paul Johnson, Rafick-Pierre Sekaly, Francois Villinger, Steve E. Bosinger, Rama Rao Amara, Vijayakumar Velu

×

Figure 4

Combination IL-12 and IL-15 cytokine treatment improves proliferative and cytotoxic capacity of CXCR5+ NK cells.

Options: View larger image (or click on image) Download as PowerPoint
Combination IL-12 and IL-15 cytokine treatment improves proliferative an...
(A and B) Pearson’s correlation between CXCR5+ NK cells (in LNs) and SHIV plasma viral RNA (n = 21) (A) and GC-Tfh (B) (n = 19). (C) GSEA revealed enriched cytokine signaling in CXCR5+ NK cells relative to CXCR5– counterparts. (D and E) Effect of in vitro stimulation with combination of IL-12 and IL-15 cytokines for 72 hours on NK cell functional properties (n = 4). (E) Frequency of NKG2A+ cells, cytokine expression, and degranulation. (F) Proliferation and granzyme expression on CXCR5+ NK cells in LNs are shown; data for 6 animals are indicated. (G) Correlation between plasma levels of IL-12 cytokines and SHIV RNA levels (n = 15). Correlation between plasma levels of IL-12 cytokines and CXCR5+ NK cells. To correct for multiple correlations, we performed Bonferroni’s correction. Assuming the overall significance level to be 0.05, the significance threshold for individual correction will be 0.05/2 = 0.025. Under this significance threshold, both comparisons are considered significant. For P value, Mann-Whitney test was used for in vitro analysis. Pearson’s correlation was used for correlation analysis.