Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

Verjans, Georges M. G. M.; Hintzen, Rogier Q.; Dun, Jessica M. van; Poot, Andreas A.; Milikan, Johannes C M; Laman, Jon D.; Langerak, Anton W.; Kinchington, Paul R.; Osterhaus, Albert D. M. E.

doi:10.1073/pnas.0610847104

Cited by 199 publications

(241 citation statements)

References 45 publications

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“…Moreover, recent studies have suggested a prominent role of tissueresident memory T cells (T RM ) in providing local protection (4). Virus-specific CD8 T RM cells have been described in sensory ganglia, skin, brain, and intestinal mucosa (4)(5)(6)(7)(8)(9)(10)(11). Common features of differently localized T RM cells are the expressions of the α E β 7 integrin CD103 and of CD69 (4,5,7,9).…”

Section: Epithelial Tissues | Viral Infectionsmentioning

confidence: 99%

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

Hofmann

Pircher

2011

Proc. Natl. Acad. Sci. U.S.A.

151

179

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The salivary glands are important effector sites for IgA-mediated humoral immunity to protect oral surfaces. Within murine submandibular glands (SMG), we identified a memory CD8 T-cell population that exhibited a unique cell-surface phenotype distinct from memory CD8 T cells in spleen but similar to memory T cells resident in the intraepithelial lymphocyte compartment of the intestinal mucosa. In mice immune to lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), virus-specific memory CD8 T cells with this unusual phenotype were present in SMG at remarkably high frequencies. LCMV-specific memory CD8 T cells in SMG showed potent functional activities in vivo, including cytokine-induced bystander proliferation, antigen-triggered IFNγ production, and viral clearance. Adoptive transfer experiments further revealed that the capacity to accumulate in SMG decreased during CD8 Tcell differentiation and that SMG CD8 T cells were poorly replenished from the circulation, indicating that they were tissue-resident. Moreover, they preferentially relocalized within their tissue of origin after adoptive transfer and antigen rechallenge, thus revealing an imprinted differentiation status. Accumulation of memory CD8 T cells within SMG did not require local antigen presentation but was promoted by the epithelial differentiation molecule E-cadherin intrinsically expressed by these CD8 T cells. This finding extends the epithelial-restricted function of E-cadherin to an impact on lymphocyte accumulation within epithelial tissues.epithelial tissues | viral infections T he establishment of a multilayered memory T-cell system provides high flexibility to combat reinfections with different pathogens. Central memory T cells (T CM ) build up a long-lasting pool of rapidly replicating cells in secondary lymphoid organs whereas effector memory T cells (T EM ) patrolling blood, spleen, and nonlymphoid tissues are crucial to fighting incoming infections by immediate effector functions (1, 2). Parabiosis experiments, however, revealed that entry of blood-borne memory T cells into brain and gut lamina propria is restricted (3). Moreover, recent studies have suggested a prominent role of tissueresident memory T cells (T RM ) in providing local protection (4). Virus-specific CD8 T RM cells have been described in sensory ganglia, skin, brain, and intestinal mucosa (4-11). Common features of differently localized T RM cells are the expressions of the α E β 7 integrin CD103 and of CD69 (4,5,7,9). Submandibular glands (SMG) are accessory organs of the oral mucosa and well-characterized effector sites of the mucosal IgA response (12, 13). In addition to B cells, SMG also accommodate αβ and γδ T cells, NK cells, and other innate immune cell populations (13, 14). The glandular tissue further represents an important target organ for cytomegalovirus infections and for autoimmune reactions (15, 16). As SMG are exocrine epithelial tissues, the epithelial differentiation molecule E-cadherin is highly expressed in these organs. E-cadh...

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Section: Epithelial Tissues | Viral Infectionsmentioning

confidence: 99%

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

Hofmann

Pircher

2011

Proc. Natl. Acad. Sci. U.S.A.

151

179

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“…In skin the immunoreactive cells responsible for controlling the transmitted HSV include the normal constituents of the squamous epidermis, keratinocytes and LC, and infiltrating cells. In particular HSV-specific CD4 and CD8 T lymphocytes play a central role in controlling primary and recurrent HSV infections in humans and in primary disease in murine models (where human specimens are difficult to obtain); in recovery from infection as well as in restricting HSV reactivation and spread in the nervous system [45][46][47][48]. In human recurrent disease, there is a temporal sequence of cellular infiltration, first predominantly monocyte/macrophages and CD4 lymphocytes and later predominantly CD8 lymphocytes, as shown by immunohistochemistry and direct T-cell cloning from lesions biopsied serially [43].…”

mentioning

confidence: 99%

Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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“…HSV-1-specific CD8 + T cells localize to the site of HSV-1 infection in human and murine trigeminal ganglia (TG) (3)(4)(5), and both HSV-specific CD8 + and CD4 + T cells localize to acute and healed sites of skin infection in mice and humans, suggesting that optimally programmed memory cells could monitor for infection or reactivation (6)(7)(8). In animals, HSV ganglionic load correlates with reactivation frequency, so pre-equipping an individual with HSV-specific CD8 + T cells could reduce seeding of the ganglia, even if a primary infection occurs in recipients of a non-sterilizing vaccine, and ameliorate the chronic disease (9,10).…”

Section: Introductionmentioning

confidence: 99%

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Jing¹,

Haas²,

Chong³

et al. 2012

J. Clin. Invest.

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Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8 + T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8 + and CD4 + T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4 + T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8 + and CD4 + T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods -also demonstrated in principle for vaccinia virus for both CD8 + and CD4 + T cells -should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens. IntroductionHerpes simplex virus type 1 (HSV-1) infects 60% of the US population and has a significant cumulative health care burden in addition to causing painful recurrent oral-labial infections. For example, brain and eye infections can cause permanent damage or blindness (1). HSV-1 also causes approximately 50% of clinical first-episode genital herpes in the United States. Vaccines for HSV that have been tested thus far have failed in clinical trials, including a recent phase III trial of an adjuvanted glycoprotein D (gD2) product (2). This vaccine elicits antibody and CD4 + T cell responses but fails to induce CD8 responses. Newer platforms can elicit CD8 + and CD4 + cells, but they require rationally selected T cell antigens. We therefore developed methods to permit measurement of both CD8 and CD4 responses to the complete HSV-1 proteome to begin rational prioritization of next-generation vaccine candidates.Several recent observations support the concept that an effective HSV vaccine will need to induce coordinated CD8 + and CD4 + T cell responses. HSV-1-specific CD8 + T cells localize to the site of HSV-1 infection in human and murine trigeminal ganglia (TG) (3-5), and both HSV-specific CD8 + and CD4 + T cells localize to acute and healed sites of skin infection in mice and humans, sug-

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Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

Cited by 199 publications

References 45 publications

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

Langerhans cells and viral immunity

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

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