Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure

Abstract

The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge.

Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion

“…PD1 is a molecule expressed upon T-cell activation, which then acts as a checkpoint to prevent exaggerated T-cell activation through interacting with its ligand, PD-L1 or PD-L2 (45). In the past few decades, PD1expressing T cells have been well-established as an exhausted Tcell population with defective function generated during chronic viral infection and tumor development (46,47). Accordingly, targeting these cells by PD1 blockade has resulted in great clinical success in cancer immunotherapy for a variety of cancer types (48).…”

MKL1 is a key biomarker correlated with immune infiltrates and chemosensitivity in breast cancer

“…The mortality rates in breast cancer have been prominently decreased by immunotherapeutic strategies, but there still remains a need to identify key genes, especially those that could modulate the compound of the TME (3,38). Increasing evidence supports that immune cells within the TME could become a significant factor in predicting therapeutic efficacy and treatment outcomes (39)(40)(41)(42). In our study, we found that MKL1 was linked with the expression of different tumor-infiltrating immune cells.…”

Interferon regulatory factor 4 deficiency in CD8+ T cells abrogates terminal effector differentiation and promotes transplant acceptance

“…We found that the transferred Irf4 ‐deficient CD8 + T cells barely differentiated into CD62L − CX3CR1 + cells when compared to those of control CD8 + T cells (Figure 4C,D). Inhibitory receptors are transiently expressed on functional effector T cells 25,26 . We found that Irf4 ‐deficient CD8 + T cells barely expressed inhibitory receptors PD‐1, TIM‐3 and LAG‐3 when compared to those of control CD8 + T cells (Figure ).…”

“…Inhibitory receptors are transiently expressed on functional effector T cells. 25,26 We found that Irf4-deficient CD8 + T cells barely expressed inhibitory receptors PD-1, TIM-3 and LAG-3 when compared to those of control CD8 + T cells ( Figure S2b-e). Taken together, IRF4 deficiency in CD8 + T cells abrogates their terminal effector differentiation in transplant recipients.…”