High Expression of CD244 and SAP Regulated CD8+ T Cell Responses of Patients with HTLV-I Associated Neurologic Disease

Enose-Akahata, Yoshimi; Matsuura, Eiji; Oh, Unsong; Jacobson, Steven

doi:10.1371/journal.ppat.1000682

Cited by 26 publications

(26 citation statements)

References 70 publications

(98 reference statements)

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“…Although the inhibitory receptors PD-1 and Lag 3 do not appear to play a role in the selective loss of secondary effectors, our data implicate 2B4 as an immunomodulatory molecule that regulates memory cell expansion or survival during persistent antigen stimulation. Consistent with 2B4 mRNA and protein being up-regulated on exhausted CD8 + T cells during chronic LCMV, increased surface expression on virus-specific CD8 + T cells is found during human chronic diseases, such as HCV, HBV, HIV, HTLV-1 and melanomas (Bengsch et al, 2010; Casado et al, 2005; Enose-Akahata et al, 2009; Raziorrouh et al, 2010; Tarazona et al, 2002). The role of 2B4 on CD8 + T cell responses has not been well studied.…”

Section: Discussionmentioning

confidence: 55%

Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load

et al. 2011

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Summary To design successful vaccines for chronic diseases, an understanding of memory CD8+ T cell responses to persistent antigen re-stimulation is critical. However, most studies comparing memory and naïve cell responses have only been performed in rapidly cleared acute infections. Herein, by comparing the responses of memory and naïve CD8+ T cells to acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we show that memory cells dominated over naïve cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, memory cells were quickly lost, unlike naïve cells. This occurred with both transgenic and endogenous memory CD8+ T cells, and with memory cells initially generated by different vaccines. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4+ T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4+ T cell help and rapidly control infection.

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Section: Discussionmentioning

confidence: 55%

Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load

et al. 2011

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“…Various studies revealed, that exhausted CD8 + T cells exhibit increased 2B4 expression during chronic human diseases such as LCMV, HBV, HCV, HIV and also melanoma [100–105]. Interestingly, the adaptor protein SAP contributes to a positive 2B4 signaling, which is higher expressed in effector T cells compared to exhausted T cells, whereas the exhausted ones display elevated 2B4 levels in chronic LCMV infection [100, 106].…”

Section: Inhibitory Receptors Associated With T Cell Exhaustionmentioning

confidence: 99%

T cell exhaustion: from pathophysiological basics to tumor immunotherapy

Klieser²,

et al. 2017

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The immune system is capable of distinguishing between danger- and non-danger signals, thus inducing either an appropriate immune response against pathogens and cancer or inducing self-tolerance to avoid autoimmunity and immunopathology. One of the mechanisms that have evolved to prevent destruction by the immune system, is to functionally silence effector T cells, termed T cell exhaustion, which is also exploited by viruses and cancers for immune escape In this review, we discuss some of the phenotypic markers associated with T cell exhaustion and we summarize current strategies to reinvigorate exhausted T cells by blocking these surface marker using monoclonal antibodies.

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“…Consistent with a role in exhaustion, in subjects chronically infected with hepatitis B virus, blockade of CD244 or CD48 resulted in enhancement of antiviral cytotoxicity and cytokine production (27). In contrast, for subjects with HTLV-I associated neurologic disease, blockade of CD244, or knockdown of the signaling molecule SAP, reduced HTLV-specific antiviral functions (28). In subjects with HIV infection, blockade of CD244 was found to enhance HIV-specific CD8 T cell proliferation from PBMC (22).…”

Section: Discussionmentioning

confidence: 99%

Simultaneous TCR and CD244 Signals Induce Dynamic Downmodulation of CD244 on Human Antiviral T Cells

Pacheco

McLean

Rohrbach

et al. 2013

The Journal of Immunology

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Various co-signaling molecules on T cells can contribute to activation, inhibition, or exhaustion, depending on context. The SLAM family receptor CD244 (2B4/SLAMf4) has been shown to be capable of either inhibitory or enhancing effects upon engagement of its ligand CD48 (SLAMf2). We examined phenotypes of CD8 T cells from HIV+ and HIVneg human donors, specific for HIV and/or respiratory syncytialvirus. Cultured and ex vivo CD8 T cells expressed PD-1, CD244, and TIM-3. We found that ex vivo CD8 T cells downregulated CD244 in response to superantigen. Furthermore cognate peptide induced rapid downregulation of both CD244 and TIM-3, but not PD-1, on CD8 T cell clones. CD244 downmodulation required simultaneous signaling via both TCR and CD244 itself. Using a pH-sensitive fluorophore conjugated to avidin-antibody tetramers, we found that CD244 crosslinking in the presence of TCR signaling resulted in rapid transport of CD244 to an acidic intracellular compartment. Downregulation was not induced by PMA-ionomycin, or prevented by PI3K inhibition, implicating a TCR-proximal signaling mechanism. CD244 internalization occurred within hours of TCR stimulation, and required less peptide than was required to induce IFNγ production. The degree of CD244 internalization varied among cultured CD8 T cell lines of different specificities, and correlated with the enhancement of IFNγ production in response to CD48 blockade in HIV+, but not HIVneg subjects. Our results indicate that rapid CD244 internalization is induced by a two-signal mechanism and plays a role in modulation of antiviral CD8 T cell responses by CD48-CD244 signaling.

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High Expression of CD244 and SAP Regulated CD8+ T Cell Responses of Patients with HTLV-I Associated Neurologic Disease

Cited by 26 publications

References 70 publications

Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load

Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load

T cell exhaustion: from pathophysiological basics to tumor immunotherapy

Simultaneous TCR and CD244 Signals Induce Dynamic Downmodulation of CD244 on Human Antiviral T Cells

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