Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo

Do, Jeong-Su; Valujskikh, Anna; Vignali, Dario A.A.; Fairchild, Robert L.; Min, Booki

doi:10.1073/pnas.1207219109

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…This is consistent with the unique profile of adipose tissue Tregs (Feuerer et al, 2009). Consistent with reports of a role for MHCII in shaping CD8 maturation (Do et al, 2012), both MMKO and MHCIIKO mice have an increase in adipose tissue CD8 + cells suggesting that an increase in CD8 + T cells in fat alone is not sufficient to potentiate insulin resistance. Moreover, MHCIIKO mice have a significant reduction in Tregs, yet are protected from obesity-induced inflammation.…”

Section: Discussionsupporting

confidence: 85%

An MHC II-Dependent Activation Loop between Adipose Tissue Macrophages and CD4+ T Cells Controls Obesity-Induced Inflammation

Cho¹,

Morris²,

DelProposto³

et al. 2014

Cell Reports

149

176

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Summary An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4+ T cells by unclear mechanisms. We have examined if interactions between adipose tissue macrophages (ATMs) and CD4+ T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHCII) showed protection from diet-induced obesity. Deletion of MHCII expression in macrophages led to an adipose tissue specific decrease in the effector/memory CD4+ T cells, attenuation of CD11c+ ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c+ ATMs in obese mice. These studies demonstrate the importance of MHC Class II restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation.

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Section: Discussionsupporting

confidence: 85%

An MHC II-Dependent Activation Loop between Adipose Tissue Macrophages and CD4+ T Cells Controls Obesity-Induced Inflammation

Cho¹,

Morris²,

DelProposto³

et al. 2014

Cell Reports

149

176

View full text Add to dashboard Cite

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“…The lower T-cell-stimulatory capacity of Ma-Mel-48b cells could not be explained by an altered expression of immunomodulatory B7 molecules or the adhesion molecule CD54. In addition, there was no expression of HLA-DR molecules, described as ligands of the regulatory receptor LAG3 (28)(29)(30)(31). Furthermore, HLA allele alterations, known to protect melanoma cells from certain T-cell specificities, were not detected in Ma-Mel-48b cells (13,15,32).…”

Section: Discussionmentioning

confidence: 98%

Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression

Sucker

Zhao

Real

et al. 2014

Clinical Cancer Research

152

108

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Purpose: CD8 þ T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells. Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell-stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor-T-cell interaction.Results: Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell-stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I-negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of b2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second b2m-deficient melanoma model. Conclusion: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell-based immunotherapy. Clin Cancer Res; 20(24); 6593-604. Ó2014 AACR.

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“…Indeed, as T cell polyfunctionality has become a recognized measure of potency, determining the extent of functional impairment of helpless CD8 T cells requires more specific measurements. In addition, CD8 T cells that mature in an environment deficient in peptide-MHC-II interactions have recently been shown to be hyperactive in their proliferative capacity in lymphopenic conditions (33). Due to these concerns, we also examined the role of CD4 help in B6 mice treated with GK1.5 MAb, which depletes CD4 T cells.…”

Section: Discussionmentioning

confidence: 99%

Promotion of a Subdominant CD8 T Cell Response during Murine Gammaherpesvirus 68 Infection in the Absence of CD4 T Cell Help

Freeman

Roberts

Burkum

et al. 2014

J Virol

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CD8 and CD4 T cells are each critically important for immune control of murine gammaherpesvirus 68 (␥HV68) infection. In immunocompetent mice, acute ␥HV68 infection results in lifelong latency, but in the absence of CD4 T cell help, mice succumb to viral recrudescence and disease. However, the requirements for CD4 T cell help in the generation and maintenance of antiviral CD8 T cell responses are incompletely understood, and it is unclear whether there are epitope-specific differences in the requirement of CD8 T cells for CD4 help. In this report, we characterized the CD8 T cell response to ␥HV68 in major histocompatibility complex (MHC) class II ؊/؊ mice, which lack CD4 T cells, or after antibody-mediated depletion of CD4 T cells. All antiviral CD8 T cells exhibited marked upregulation of surface expression of the inhibitory receptor programmed death-1 (PD-1), but surprisingly, while the immunodominant memory response appeared to be functionally impaired, helpless CD8 T cells of a subdominant specificity had increased numbers and enhanced functionality. Thus, we demonstrate differential requirements for CD4 help in the antiviral CD8 T cell response to a latent gammaherpesvirus. IMPORTANCE␥HV68 is a mouse pathogen closely related to the oncogenic human ␥HVs, which infect a majority of the world's population. Reactivation of these viruses from latency can lead to complications, disease, and even death. CD4 T cells are required for complete immune control of long-term infection, in part by providing key signals to dendritic cells that in turn instruct optimal antiviral CD8 T cell responses. We have investigated multiple virus-specific CD8 T cell responses during infection and identified a subdominant CD8 T cell response that is numerically and functionally enhanced in the absence of CD4 T cell help. This occurs in spite of high surface expression of an inhibitory receptor and in contrast to the immunodominant response, which is impaired. Our data suggest that signals from CD4 T cells are important in maintaining the CD8 T cell hierarchy during ␥HV infections.T he human gammaherpesviruses (␥HVs) are ubiquitous and present a considerable public health risk by establishing lifelong latent infections. Under conditions of immunosuppression, such as HIV coinfection, ␥HVs can reactivate from latency, leading to recurrent disease, transplantation complications, and cancers (1). The human ␥HVs are tightly species specific, making studies of their in vivo pathogenesis and of virus-specific immunity difficult. Intranasal (i.n.) infection of mice with the natural rodent pathogen murine ␥HV68 provides a tractable small-animal model of human ␥HV pathogenesis and immunity.CD8 and CD4 T cells are critically important for long-term survival of ␥HV68-infected mice. Mice deficient in either CD8 or CD4 T cells succumb to infection, albeit with different kinetics, and both CD8 and CD4 T cells contribute to the long-term control of viral latency (2-5). In some models of viral infection, CD4 T cells are critically important for ...

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Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo

Cited by 15 publications

References 23 publications

An MHC II-Dependent Activation Loop between Adipose Tissue Macrophages and CD4+ T Cells Controls Obesity-Induced Inflammation

An MHC II-Dependent Activation Loop between Adipose Tissue Macrophages and CD4+ T Cells Controls Obesity-Induced Inflammation

Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression

Promotion of a Subdominant CD8 T Cell Response during Murine Gammaherpesvirus 68 Infection in the Absence of CD4 T Cell Help

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