NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division
Linda Borst1, Marjolein Sluijter1, Gregor Sturm2
1Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
Abstract:
The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A+ CD8 T cell population in the context of other inhibitory receptors. Here we used a well-controlled culture system to study the kinetics of inhibitory receptor expression. Naïve mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL-7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD-1, TIGIT and LAG-3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM-3 and CD39. Importantly, single-cell transcriptomics of human tumor-infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF-β in vitro, although TGF-β signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD-1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM-3 and CD39, NKG2A might thus mark actively dividing tumor-specific TILs.
Insights
NKG2A is a late inhibitory receptor on CD8 T cells, emerging after repeated antigen exposure, unlike PD-1 which signals recent T cell activation. NKG2A, TIM-3, and CD39 may identify actively dividing tumor-specific T cells.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- The inhibitory receptor NKG2A (CD94/NKG2A) is expressed on a subset of CD8 T cells.
- Antibodies targeting NKG2A are in clinical trials for cancer immunotherapy.
- Characterizing NKG2A+ CD8 T cells alongside other inhibitory receptors is crucial.
Purpose of the Study:
- To investigate the expression kinetics of NKG2A on CD8 T cells.
- To compare NKG2A expression patterns with other inhibitory receptors like PD-1, TIGIT, and LAG-3.
- To determine the potential role of NKG2A in identifying specific T cell populations in tumors.
Main Methods:
- Naïve mouse CD8 T cells were repeatedly activated in vitro using artificial antigen-presenting cells and IL-7.
- Expression of inhibitory receptors (NKG2A, PD-1, TIGIT, LAG-3, TIM-3, CD39) was analyzed over time.
- Single-cell transcriptomics of human tumor-infiltrating lymphocytes (TILs) was performed.
- NKG2A expression was studied in relation to cell division and TGF-β signaling in vitro and in vivo.
Main Results:
- NKG2A expression was induced late, after repeated antigen stimulation, distinguishing it from rapidly induced and downregulated receptors PD-1, TIGIT, and LAG-3.
- The expression kinetics of NKG2A resembled those of TIM-3 and CD39.
- Human TIL analysis revealed co-expression of NKG2A with TIM-3 and CD39 on CD8 T cell clusters.
- NKG2A expression correlated with cell division and was promoted by TGF-β in vitro.
Conclusions:
- NKG2A represents a late inhibitory receptor, induced by sustained antigen stimulation, contrasting with PD-1's indication of recent T cell activation.
- NKG2A, along with TIM-3 and CD39, may serve as a marker for actively dividing tumor-specific T cells.
- These findings provide insights into the heterogeneity of CD8 T cell responses in cancer immunotherapy.
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