Date Published: February 8, 2018
Publisher: Public Library of Science
Author(s): Catia T. Perciani, Walter Jaoko, Bashir Farah, Mario A. Ostrowski, Omu Anzala, Kelly S. MacDonald, Aftab A. Ansari.
Cell surface expression of α4β7, α4β1 and αEβ7 integrins play a key role in T cell distribution. Understanding the contribution of integrins to the density and ratios of CD4+: CD4negT cell at the portals of entry for HIV is of fundamental importance for the advance of more effective HIV prevention strategies. We therefore set out to characterize and compare the expression of α4β7, α4β1 and αEβ7 integrins on systemic, cervical and rectal CD4+ and CD4negT cells isolated from a cohort of healthy Kenyan women at low risk for sexually transmitted infections (STI) (n = 45). Here we show that blood and cervix were enriched in α4+β1+CD4+T cells and α4+β7hiCD4+T cells, whereas the rectum had an equal frequency of α4+β7hiCD4+T cells and αE+β7hiCD4+T cells. Most cervical and rectal αE+β7hiCD4+T cells expressed CCR5 as well as CD69. Interestingly, αEβ7 was the predominant integrin expressed by CD4negT cells in both mucosal sites, outnumbering αE+β7hiCD4+T cells approximately 2-fold in the cervix and 7-fold in the rectum. The majority of αE+β7hiCD4negT cells expressed CD69 at the mucosa. Taken together, our results show unique tissue-specific patterns of integrin expression. These results can help in guiding vaccine design and also the use of therapeutically targeting integrin adhesion as a means to preventing HIV.
Most HIV transmission globally occurs through sexual intercourse. Scrutinizing the events associated with the influx of activated CCR5+CD4+T cells into the genital and gut mucosa and the maintenance of a pool of HIV-specific effector memory CD8+T cells at the portal of entry to HIV can inform HIV vaccine and therapy design. Integrins are αβ heterodimeric, transmembrane proteins that among other functions, direct cell trafficking and retention at various anatomical sites . Among the 24 αβ integrin pairs identified to date, three of them are especially important for T cell localization: α4β7, αEβ7 and α4β1. α4β7 integrin binds predominantly to MAdCAM-1 (mucosal addressin cell adhesion molecule-1), a molecule expressed on endothelial cells of the gastrointestinal and genital tract, and it is well known as a gut-homing marker . αEβ7 binds to E-cadherin and plays a role on T cell retention in epithelial tissues such as skin and gut [3, 4]. α4β1 integrin, also named VLA-4 (very late antigen-4), is expressed on monocytes and lymphocytes, but in contrast to the first two integrins is also expressed on many other cell types. α4β1 binds to VCAM-1 (vascular cell adhesion protein-1) and can direct cell migration to a diverse set of sites, including the genital tract, gut, lungs and brain.
The distribution of T cells in mucosal tissues directly impacts on protection against pathogens as well as disease outcome. The availability of activated CCR5+CD4+ T cells is known to increase susceptibility to HIV infection [29, 30]. In addition, CD4+T cell depletion in HIV infected individuals leads to a pronounced impairment of their gut-associated lymphoid tissue (GALT) function which is not reversed even after viral suppression with ART [31–34]. Therefore, understanding the distinct integrin expression that mediated cell migration and retention may assist in targeting HIV at the mucosa and restore gut immunity.