Modulating T Cell Responses via Autophagy: The Intrinsic Influence Controlling the Function of Both Antigen-Presenting Cells and T Cells

Merkley, Seth D.; Chock, Cameron J.; Yang, Xuexian O.; Harris, James; Castillo, Eliseo F.

doi:10.3389/fimmu.2018.02914

Cited by 50 publications

(37 citation statements)

References 257 publications

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“…Stimulation of T lymphocyte receptors or HIV infection induces autophagy activation in vitro. The study found that thymic epithelial cells in the thymic cortex of mice have high levels of autophagic activity, suggesting that autophagy plays a role in the development and selection of T lymphocytes (Merkley et al 2018).…”

Section: Overviewmentioning

confidence: 90%

Autophagy and the Immune Response

Cui

Lin

et al. 2019

Autophagy: Biology and Diseases

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Innate immunity and adaptive immunity play critical roles in maintaining normal physiological functions and the development of diseases. In innate immune responses, heterogeneous autophagy can directly remove intracellular pathogens while activating PRRs, including TLRs and NLRs, to trigger their signal transduction pathways and promote NKT cell activation, cytokine secretion, and phagocytosis. In adaptive immune responses, the autophagy reaction has an important effect on the homeostasis, function, and differentiation of T lymphocytes, the survival, and development of B lymphocytes and the survival of plasma cells. This review highlights the key role that autophagy plays in the innate immune system and the acquired immune system. Further clarifying the mechanism by which autophagy regulates the immune system is essential for elucidating the precise mechanisms of various diseases and for developing new treatment methods.

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Section: Overviewmentioning

confidence: 90%

Autophagy and the Immune Response

Cui

Lin

et al. 2019

Autophagy: Biology and Diseases

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“…In addition, although the percentage of CD4 + T cells was increased under treatment of CCL-34 and CCL-34 plus 3-MA, the functions of T cells in vivo were not examined in our study. Considering the critical role of autophagy in regulating T cell responses 6 , whether the functions of CCL-34-induced T cells are suppressed by 3-MA in vivo can be further explored in the future. Taken together, our data indicate that CCL-34 regulates both LPM and SPM functions and induces the percentage of CD4 + T cell which is similar to the immune stimulating response of LPS.…”

Section: Discussionmentioning

confidence: 99%

“…above, autophagy regulates T cell responses via direct modulation of T cells and indirect modulation of APCs 6 . Therefore, autophagy-promoting agents may serve as potential vaccine/adjuvants candidates to enhance immune responses 24,25 .…”

mentioning

confidence: 98%

Vaccine adjuvant activity of a TLR4-activating synthetic glycolipid by promoting autophagy

Chou

Lin²,

Dzhagalov³

et al. 2020

Sci Rep

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Toll-like receptors (TLRs) play crucial roles in host immune defenses. Recently, TLR-mediated autophagy is reported to promote immune responses via increasing antigen processing and presentation in antigen presenting cells. The present study examined whether the synthetic TLR4 activator (CCL-34) could induce autophagy to promote innate and adaptive immunity. In addition, the potential of CCL-34 as an immune adjuvant in vivo was also investigated. Our data using RAW264.7 cells and bone marrow-derived macrophages showed that CCL-34 induced autophagy through a TLR4-NF-κB pathway. The autophagy-related molecules (Nrf2, p62 and Beclin 1) were activated in RAW264.7 cells and bone marrow-derived macrophages under CCL-34 treatment. CCL-34-stimulated macrophages exhibited significant antigen-processing activity and induced the proliferation of antigen-specific CD4+T cells as well as the production of activated T cell-related cytokines, IL-2 and IFN-γ. Furthermore, CCL-34 immunization in mice induced infiltration of monocytes in the peritoneal cavity and elevation of antigen-specific IgG in the serum. CCL-34 treatment in vivo did not cause toxicity based on serum biochemical profiles. Notably, the antigen-specific responses induced by CCL-34 were attenuated by the autophagy inhibitor, 3-methyladenine. In summary, we demonstrated CCL-34 can induce autophagy to promote antigen-specific immune responses and act as an efficient adjuvant. Vaccine development holds a great contribution in infectious disease prevention and cancer immunotherapy. Vaccines contain both antigens and adjuvants to induce antigen (Ag)-specific antibody responses. Adjuvants are required to boost Ag-specific adaptive immune response in B cells and T cells. The current strategies of vaccine development to trigger early immune responses are via enhancing Ag uptake in antigen-presenting cells (APCs), providing appropriate microenvironments for APC activations, and further promoting the differentiation of naïve T cells into effector T cells 1,2. Currently licensed adjuvants in clinical applications, such as AS04, MF59 and Alum, were reported to activate pattern recognition receptors (PRRs) and/or NLRP3 inflammasome, which trigger humoral antibody responses accompanied with T cell responses 1,3-5. Recent studies showed that stimulation of autophagy is able to augment T cell responses via modulating the functions in both APCs and T cells 6. The autophagy/lysosome degradation pathway is an evolutionarily conserved stress response mechanism for survival 7 , and its dysregulation plays critical roles in human diseases 8. During infection, one of the major immune mechanisms against pathogens is to induce canonical and noncanonical autophagy in macrophages. The canonical selective autophagy (xenophagy) selectively captures and degrades intracellular mycobacteria, such as Mycobacterium tuberculosis and Listeria monocytogenes 9,10. Moreover, the noncanonical autophagy, LC3-associated phagocytosis (LAP), can accelerate pathogen clearance 11-15. Furthermore, induction o...

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“…Autophagy also functions in the presentation of MHC class I-restricted antigens, which stimulate CD8 + T cells. Autophagy in APC can, therefore, greatly influence the responses of T cell subsets via both MHC I and II-dependent antigenic presentations [ 47 ].…”

Section: Autophagy and Immune Responsesmentioning

confidence: 99%