SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation

Chemnitz, Jens M.; Parry, Richard V.; Nichols, Kim E.; June, Carl H.; Riley, James L.

doi:10.4049/jimmunol.173.2.945

Cited by 1,007 publications

(890 citation statements)

References 56 publications

(66 reference statements)

Supporting

Mentioning

842

Contrasting

Unclassified

Order By: Relevance

“…21 PD-1 1 tumor-infiltrating CD8 1 T cells leads to decreased proliferation and downregulated IL-2 and IFN-c production possibly by downregulating the T-cell receptor signal through phosphatase SHP-1 and SHP-2 recruitment. 28 It has been reported that PD-1 may exert its effects directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. 29 In our study, we did not detect upregulation of cytotoxic T lymphocyte-associated antigen 4 or downregulation of CD28 (data not shown) on tumor-infiltrating CD8 1 T cells, so cytotoxic T lymphocyte-associated antigen 4 and CD28 are unlikely to be contributing to the CD8 1 T-cell defects.…”

Section: Discussionmentioning

confidence: 99%

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

View full text Add to dashboard Cite

T-cell tolerance is an important mechanism for tumor escape, but the molecular pathways involved in T-cell tolerance remain poorly understood. It remains unknown whether the inhibitory immunoreceptor programmed death-1 (PD-1) plays a role in conditions of human non-small cell lung cancer (NSCLC). In this study, we detected PD-1 expression on CD8 1 T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8 1 T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD8 1 T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

View full text Add to dashboard Cite

show abstract

“…However, SHP-2 does associate with a variety of ITIM-containing T cell inhibitory receptors, including CTLA-4 (48, 49), programmed death 1 (PD-1; Ref. 50), and B and T lymphocyte attenuator (BTLA; Ref 51). Because SHP-2 has been implicated in both inhibitory (52,53) and stimulatory (54,55) signaling cascades, its contribution to CEACAM1-dependent effects must still be defined.…”

Section: Discussionmentioning

confidence: 99%

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

Lee

Ostrowski

Gray-Owen

2008

The Journal of Immunology

View full text Add to dashboard Cite

Neisseria gonorrhoeae colony opacity-associated (Opa) proteins bind to human carcinoembryonic antigen cellular adhesion molecules (CEACAM) found on host cells including T lymphocytes. Opa binding to CEACAM1 suppresses the activation of CD4+ T cells in response to a variety of stimuli. In this study, we use primary human CD4+ T cells isolated from peripheral blood to define the molecular events occurring subsequent to Opa-CEACAM1 binding. We establish that, in contrast to other cell types, T cells do not engulf N. gonorrhoeae upon CEACAM1 binding. Instead, the bacteria recruit CEACAM1 from intracellular stores and maintain it on the T cell surface. Upon TCR ligation, the co-engaged CEACAM1 becomes phosphorylated on tyrosine residues within the ITIMs apparent in the cytoplasmic domain. This allows the recruitment and subsequent activation of the src homology domain 2-containing tyrosine phosphatases SHP-1 and SHP-2 at the site of bacterial attachment, which prevents the normal tyrosine phosphorylation of the CD3ζ-chain and ZAP-70 kinase in response to TCR engagement. Combined, this dynamic response allows the bacteria to effectively harness the coinhibitory function of CEACAM1 to suppress the adaptive immune response at its earliest step.

show abstract

“…Loss of SHP-1 enhances CTL function and increases the formation of CD8 + T cell-APC contact [58]. In addition to its direct effects on TCR signaling, SHP-1 can associate with the suppressive coregulatory molecule programmed death 1 molecule (PD-1, CD279), which also inhibits T cell activation [59].…”

Section: Role Of Signaling Molecules In T Cell Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

View full text Add to dashboard Cite

The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

show abstract

SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation

Cited by 1,007 publications

References 56 publications

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Contact Info

Product

Resources

About