The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients

Efficient antitumor immune response requires the coordinated function of integrated immune components, but is finally exerted by the differentiated effector tumor-infiltrating lymphocytes (TIL). TIL cells comprise, therefore, an exciting platform for adoptive cell transfer (ACT) in cancer. In this study, we show that the inhibitory carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) protein is found on virtually all human TIL cells following preparation protocols of ACT treatment for melanoma. We further demonstrate that the CEACAM1 homophilic interactions inhibit the TIL effector functions, such as specific killing and IFN-γ release. These results suggest that CEACAM1 may impair in vivo the antitumor response of the differentiated TIL. Importantly, CEACAM1 is commonly expressed by melanoma and its presence is associated with poor prognosis. Remarkably, the prolonged coincubation of reactive TIL cells with their melanoma targets results in increased functional CEACAM1 expression by the surviving tumor cells. This mechanism might be used by melanoma cells in vivo to evade ongoing destruction by tumor-reactive lymphocytes. Finally, CEACAM1-mediated inhibition may hinder in many cases the efficacy of TIL ACT treatment of melanoma. We show that the intensity of CEACAM1 expression on TIL cells constantly increases during ex vivo expansion. The implications of CEACAM1-mediated inhibition of TIL cells on the optimization of current ACT protocols and on the development of future immunotherapeutic modalities are discussed.

Section: Inhibition Of Human Tumor-infiltrating Lymphocyte Effector Fmentioning

confidence: 81%

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

Markel

Seidman

Stern

et al. 2006

“…This may suggest that the unexpectedly low level of N. gonorrhoeae Ab that is apparent may primarily result from T-independent B cell responses; however such studies await to be performed. It is also important to consider that CEACAM1 can be expressed by all leukocytes, and its ability to elicit inhibitory signals has been established in B cells and NK cells (30,31,56). This suggests that the capacity of gonococci to bind CEACAM1 has the potential to inhibit the global immune response at multiple levels.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Ostrowski

Gray-Owen

2008

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.

“…Potentially, the quantitative PCR assay may not have recognized an allelic variant of KIR2DL1, although this was not confirmed by sequence analysis of complimentary DNA from the clone. Alternatively, as the clone did not lyse the autologous BLCL, a different receptor, such as CEACAM1 (43), may provide the inhibitory signal that prevents autoreactivity. Although we cannot completely exclude the induction of NKG2A during the culture techniques (44), this is unlikely for two reasons: all NK cell clones were cultured under the same conditions, and we observed substantially different levels of NKG2A expression; and NK cells cultured under these conditions previously have been shown to have stable receptor repertoires (16).…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Brooks

Elliott

Parham

et al. 2006

Signals transduced by inhibitory receptors that recognize self-MHC class I molecules prevent NK cells from being activated by autologous healthy target cells. In order for NK cells to be activated upon contact with an infected cell, the balance between the activating and inhibitory signals that regulate NK cell function must be altered in favor of activation. By studying liver-derived NK cells, we show that only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E. These data demonstrate that release from an inhibitory receptor:ligand interaction is one mechanism that permits NK cell recognition of a virally infected target, and that the variegated expression of inhibitory receptors in humans generates a repertoire of NK cells with different antiviral potentials.