View Abstract

A6240 - Signaling Lymphocytic Activation Molecule Family (SLAMF) Receptors May Act as Inhibitory Receptors in the Airways of HIV-Infected Individuals
Author Block: A. K. Dickey1, Y. Pacheco2, B. Corleis2, A. Schiff2, A. C. Lisanti2, B. D. Medoff1, J. L. Cho1, D. G. Kavanagh2, W. A. Burgers3, R. J. Wilkinson3, F. Tafesse2, S. Fortune2, D. S. Kwon2; 1Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA, United States, 2Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States, 3University of Cape Town, Cape Town, South Africa.
Rationale:
In people living with human immunodeficiency virus (HIV), infection with respiratory pathogens is an important cause of morbidity and mortality. Alveolar macrophages (AMs) are the predominant immune cell in the airways in non-disease states and are thought to act as the initial defense against pulmonary pathogens, including Mycobacterium tuberculosis.
The six signaling lymphocytic activation molecule family (SLAMF) receptors are a newly-described group of receptors on hematopoietic cells which associate with the SLAM-associated protein (SAP) family of adaptors. SLAMF receptors function not only as co-stimulatory molecules but also as microbial sensors controlling phagolysosomal function. While these receptors are often activating, they may be inhibitory. The important of these receptors in defense against infection is demonstrated by individuals with naturally occurring defects in SLAMF receptor signaling who develop X-linked lymphoproliferative (XLP) disease and are subject to lethal EBV infection.
Methods:
RNA sequencing was performed on AMs obtained by bronchoalveolar lavage (BAL) from individuals with and without untreated HIV infection living in Cape Town, South Africa. In a Boston cohort, flow cytometry of SLAM receptors was performed on AMs from patients without treated HIV infection and healthy controls. AMs were stimulated with lipopolysaccharide (LPS) along with SLAMF blockade antibodies. TNFα was measured by ELISA of cell culture supernatants. CRISPR/CAS knockout of SLAMF6 and SLAMF7 was performed in THP1 cells followed by stimulation with TLR agonists.
Results:
In a cohort of individuals from Cape Town, South Africa, SLAMF receptors and SAP were transcriptionally upregulated in AMs from individuals with untreated HIV-infection relative to those without HIV. Similarly, surface expression of SLAMF1, SLAMF4, and SLAMF6 was increased on AMs in a Boston cohort of subjects with treated HIV relative to uninfected controls. To evaluate the role of these receptors in airway immunology, a cocktail of SLAMF blocking antibodies were added to LPS-treated control AMs, resulting in increased TNFα secretion when compared to those treated with an IgG isotype control. Furthermore, in THP1 cells with CRISPR/CAS knockout of SLAMF6 or SLAMF7, stimulation with TLR2 and TLR4 agonists resulted in increased TNFα secretion as compared to control THP1 cells.
Conclusion:
SLAMF receptors are up regulated on AMs in HIV infection and may act as inhibitory immune receptors in the airways. These receptors may contribute to the increased susceptibility to respiratory infections observed in people living with HIV.