Circulating herpes simplex type 1 (HSV-1)-specific CD8+T cells do not access HSV-1 latently infected trigeminal ganglia

Abstract

BackgroundTherapeutic vaccines can be designed to enhance existing T cell memory populations for increased protection against re-infection. In the case of herpes simplex virus type 1, recurrent disease results from reactivation of latent virus in sensory ganglia, which is controlled in part by a ganglia-resident HSV-specific memory CD8+ T cell population. Thus, an important goal of a therapeutic HSV-1 vaccine would be to enhance this population.MethodsHSV-1-infected mice were treated with TAK-779 to block CCR5- and CXCR3-mediated CD8+ T cell migration during both acute and latent infections. Additionally, HSV-1-specific CD8+ T cells were transferred into HSV-1 latently infected mice to mimic the effect of a therapeutic vaccine, and their migration into trigeminal ganglia (TG) was traced during steady-state latency, or during recovery of the TG-resident memory CD8+ T cell population following stress-, and corticosterone-induced depletion and HSV-1 reactivation from latency. Bromodeoxy uridine (BrdU) incorporation measured cell proliferation in vivo.ResultsTAK-779 treatment during acute HSV-1 infection reduced the number of infiltrating CD8+ T cells but did not alter the number of viral genome copies. TAK-779 treatment during HSV latency did not affect the size of the TG-resident memory CD8+ T cell population. Transferred HSV-specific CD8+ T cells failed to access latently infected TG during steady-state latency, or during recovery of the TG resident HSV-specific CD8+ T cell population following exposure of latently infected mice to stress and corticosterone. Recovery of the HSV-specific CD8+ T cell population after stress and corticosterone treatment occurred with homeostatic levels of cell division and did not require CD4+ T cell help.ConclusionsOur findings are consistent with the notion that the CD8+ T cells in latently infected TG are a tissue-resident memory (Trm) population that is maintained without replenishment from the periphery, and that when this population is disrupted, it recovers without proliferation or detectable recruitment of HSV-specific CD8+ T cells from the blood. The compartmentalization of the HSV-specific CD8+ memory T cell population in latently infected TG will complicate the design of therapeutic vaccines.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…The study demonstrated that both shedding of reactivated virus in tears and recurrent corneal HSV can be induced following UV-B exposure of latently infected HLA Tg mice. Moreover, considering the wealth of data addressing the protective mechanisms of CD8 ϩ T cells specific to mouse HSV-1 epitopes (mostly the gB 498-505 epitope in B6 mice), it is surprising how few reports exist exploring the protective mechanisms of CD8 ϩ T cells specific to human HSV-1 epitopes (27,54,58,59). Our "humanized" HLA Tg mice express the human HLA-A*0201 molecule, instead of mouse H2 b major histocompatibility complex (MHC) molecules (4).…”

Immunological memories of the bone marrow

“…“Tissue‐resident” memory T cells have downregulated S1PR1, like CD69 + bone marrow memory T cells 33. “Tissue‐resident” memory T cells, despite expressing CD69, rest in terms of proliferation and expression of effector molecules 160, 163. “Tissue‐resident” memory CD8 + T lymphocytes have a typical gene expression signature, and express the transcription factor Hobit 134, 159.…”

Tissue-Resident Memory T Cells and Fixed Immune Surveillance in Nonlymphoid Organs

“…Specifically, T RM cells offer superior functionality in settings of persisting infection, especially during periods of latency when inflammation and recruitment from the blood has been extinguished. Such dissociation from the recirculating memory pool is seen during latent HSV infection (85), which is also likely to feature Ag expression that is too low for the activation and recruitment of circulating T cells (86). In addition, this specialization probably extends to the final stages of cleared infection, when pathogen load has declined to otherwise undetectable levels (40,58).…”