The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

Abstract

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8⁺ TRM, there has recently been increased interest in defining the phenotype and the role of CD4⁺ TRM in diseases. Circulating CD4⁺ T cells seed CD4⁺ TRM, but there also appears to be an equilibrium between CD4⁺ TRM and blood CD4⁺ T cells. CD4⁺ TRM are more mobile than CD8⁺ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8⁺ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4⁺ and CD8⁺ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8⁺ T cells. The exact role of the CD4⁺/CD8⁺ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4⁺ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4⁺ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4⁺ TRM and their induction by vaccines may help control sexual transmission by both viruses.

Keywords: HIV-1; HSV-1/2; immunity; infection; keratitis; tissue resident CD4+, CD8+, vaccines.

Figure 1

The linear model of progressive differentiation. (A) The differentiation of a naïve T cells (TN) cell into an activated phenotype that ultimately results in cell death. Once a CD4⁺ T cell reaches its full differentiation potential, and depending on stimuli, it can be defined as one of seven major effector helper subsets, with distinct surface markers, cytokine secretion profiles and overall functions. (B) As a cell progresses down this linear path, it may diverge at any point depending on the strength and consistency of the stimulus. This divergence results in a memory cell phenotype depending on the early level of differentiation the cell has already experienced. These memory cells are defined by the expression of a range of surface markers and are distinguished by the strength of effector functions and proliferative capacities. According to this model, once a memory cell is reactivated, the cell must only travel down the linear progression to become a short-lived effector T cell (TEFF). This process cannot be reversed to an earlier subset.

Figure 2

A summary of the role of resident memory T cells in the mouse and human genital mucosa especially during herpes simplex virus (HSV) infection.

Figure 3

Summary of the key dynamics amongst CD4⁺ T cell subsets during HIV infection in relevant anatomical compartments. Figure created with BioRender.com.