Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence

Cush, Stephanie S.; Anderson, Karen K.; Ravneberg, David; Weslow-Schmidt, Janet L.; Flaño, Emilio

doi:10.4049/jimmunol.179.1.141

Cited by 36 publications

(48 citation statements)

References 102 publications

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“…It should also be noted that during late latency, the percentage of specific lysis in vivo in the absence of CD8 T cells increases modestly, from 12% to 23%, as latent infection progresses (Fig. 3C), which is in stark contrast to the pattern of CD8 T-cell-mediated cytotoxicity, which peaks early during infection and is followed by a dramatic reduction by 3 months postinfection (6,16). These experiments indicate that CD8 T cells do not make a significant contribution to the killing of ␥HV68-loaded targets during an in vivo cytotoxicity assay.…”

mentioning

confidence: 54%

CD4 T Cells Mediate Killing during Persistent Gammaherpesvirus 68 Infection

Stuller

Flaño

2009

J Virol

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CD4 T cells are critical for the control of gammaherpesvirus persistence, but their direct effector mechanisms of virus control in vivo are still poorly understood. In this study, we use murine gammaherpesvirus 68 (␥HV68) in in vitro and in vivo cytotoxicity assays to show CD4-dependent killing of ␥HV68-loaded cells in mice persistently infected with ␥HV68. Our results underscore the cytotoxic capacity of CD4 T cells during ␥HV68 persistence.There is mounting evidence that during chronic or persistent viral infections, effector CD4 T cells have the ability to display cytotoxic characteristics (7,8,18). CD4 T cells with cytotoxic potential have been characterized during persistent human immunodeficiency virus and human cytomegalovirus infections (2,4,19). There are also extensive reports describing antigenspecific cytolytic CD4 T-cell cultures during persistent EpsteinBarr virus infection in humans (1,9,10,12,13,17). Whether effector CD4 T cells use cytotoxic abilities and/or other mechanisms to eliminate virus-infected cells during persistent gammaherpesvirus infection in vivo remains unknown.We first analyzed the existence of CD4 T cells with a cytotoxic phenotype in mice persistently infected with gammaherpesvirus 68 (␥HV68) (1,000 PFU in 30 l of phosphate-buffered saline, administered intranasally). Reduced surface expression of CD27 has been used as a marker of cytotoxic T cells (2). As shown in Fig. 1, the frequency of CD4 T cells lacking cell surface expression of CD27 increases from 10% in noninfected mice to 40% in the spleens and 80% in the lungs of mice at 3 months after ␥HV68 infection. The loss of CD27 expression during ␥HV68 herpesvirus latency suggested an increase in the frequency of CD4 T cells that may have a cytolytic phenotype. Next, we sought to analyze the potential of CD4 T cells to act as killers. We used CD107a and CD107b (CD107a/b) cell surface mobilization as an indicator of in vitro degranulation associated with cytolytic function (3). Splenocytes (10 6 ) obtained from the spleens of naive or long-term ␥HV68-infected mice were incubated with anti-CD28 (clone 37.51), anti-CD49d (clone 9C10 [MRF4.B]), anti-CD107a (clone 1D4B), and anti-CD107b (clone ABL-93) and stimulated with 2 g/ml of gp150 67-83 peptide, whole ␥HV68 virus (multiplicity of infection [MOI], 10), or phorbol myristate acetate/ionomycin or not stimulated (Fig. 1C). The cell suspensions were incubated for 1 h at 37°C followed by an additional 4 h in the presence of the secretion inhibitor monensin, and cell surface expression levels of CD4 (clone GK1.5), CD8 (clone 53.6.72), and CD107a/b were determined by flow cytometry. The data show that CD4 T cells isolated from the spleens of latently infected mice mobilize significantly more CD107a/b to the cell surface (4%) than their naïve counterparts (2%) (Fig. 1D). The pattern of degranulation of CD4 T cells isolated from ␥HV68-infected mice was similar in the presence or absence of exogenous in vitro restimulation. These results show that there is a statistically significant dif...

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confidence: 54%

CD4 T Cells Mediate Killing during Persistent Gammaherpesvirus 68 Infection

Stuller

Flaño

2009

J Virol

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“…Unlike naive T cells, homeostasis of memory CD8 + T cells occurs independently of antigen and MHC-I and utilizes cytokines IL- 7 and IL-15 (14,15,(18)(19)(20)(21). It has been suggested that persisting antigen might help sustenance of effector and memory CD8 + T cells (36,37). Thus, it was possible that homeostatic maintenance of helpless antifungal memory CD8 + T cells benefited from the presence of persisting vaccine antigen in our model.…”

Section: Discussionmentioning

confidence: 85%

Protective antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cell help and cognate antigen in mice

et al. 2012

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Individuals who are immunocompromised, including AIDS patients with few CD4 + T cells, are at increased risk for opportunistic fungal infections. The incidence of such infections is increasing worldwide, meaning that the need for antifungal vaccines is increasing. Although CD4 + T cells play a dominant role in resistance to many pathogenic fungal infections, we have previously shown that vaccination can induce protective antifungal CD8 + T cell immunity in the absence of CD4 + T cells. However, it has not been determined whether vaccine-induced antifungal CD8 + T cell memory can be maintained in the absence of CD4 + T cell help. Here, we have shown in a mouse model of vaccination against blastomycosis that antifungal memory CD8 + T cells are maintained in the absence of CD4 + T cells without loss of numbers or function for at least 6 months and that the cells protect against infection. Using a system that enabled us to induce and track antigen-specific, antifungal CD8 + T cells, we found that such cells were maintained for at least 5 months upon transfer into naive mice lacking both CD4 + T cells and persistent fungal antigen. Additionally, fungal vaccination induced a profile of transcription factors functionally linked with persistent memory in CD8 + T cells. Thus, unlike bacteria and viruses, fungi elicit long-term CD8 + T cell memory that is maintained without CD4 + T cell help or persistent antigen. This has implications for the development of novel antifungal vaccine strategies effective in immunocompromised patients.

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“…Limited TCR stimulation by self antigens could also play a role, as memory T cells that receive constant stimulation by exogenously administered foreign peptide antigen become impaired in their tumoricidal function (40). Alternatively, memory in vitiligo-affected mice may more closely resemble responses in hosts with chronic gammaherpesvirus or Trypanosoma cruzi infection, wherein T cells maintain an effector memory phenotype, resist functional exhaustion (41), and can provide protection in the face of persisting antigen (42)(43)(44). While classical T EM cells are thought to convert to T CM cells with time (45), the ontogeny of vitiligo-associated memory T cells remains unclear, although a small T CM population may play a role in maintaining the response.…”

Section: Figurementioning

confidence: 99%

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

Byrne¹,

Côté²,

Zhang³

et al. 2011

J. Clin. Invest.

105

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A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8 + T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4 + T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8 + memory T cells specific for shared melanoma/melanocyte antigens. CD8 + T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8 + T cell immunity to melanoma. Vitiligo-associated memory CD8 + T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

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Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence

Cited by 36 publications

References 102 publications

CD4 T Cells Mediate Killing during Persistent Gammaherpesvirus 68 Infection

CD4 T Cells Mediate Killing during Persistent Gammaherpesvirus 68 Infection

Protective antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cell help and cognate antigen in mice

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

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