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