MOLECULAR MECHANISMS OF ADAPTIVE IMMUNITY AGAINST INFECTIONS

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00567901" target="_blank" >RIV/68378050:_____/22:00567901 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.ccsss.cz/index.php/ccsss/issue/view/37/67" target="_blank" >http://www.ccsss.cz/index.php/ccsss/issue/view/37/67</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

MOLECULAR MECHANISMS OF ADAPTIVE IMMUNITY AGAINST INFECTIONS

Popis výsledku v původním jazyce

T cells are the major orchestrators of the adaptive immune responses against pathogenic bacteria and virus by inducing direct cytotoxicity (CD8+T cells) and by instructing the antibody production by B cells (CD4+T cells). On the other hand, the overt activation of the adaptive immunity leads to collateral damage to tissues and to the development of autoimmune diseases. Thus, the understanding of the molecular mechanisms of T-cell activation and regulation is crucial for desigining the therapeutic modulators of the immune response.LCK is a major protein tyrosine-kinase associated with the T-cell antigen receptor (TCR) triggering. It is bound to CD4 and CD8 co-receptors, which facilitate the TCR activation. We have generated novel mouse models to elucidate the role of CD8-LCK and CD4-LCK interaction. Surprisingly, we observed much greater importance of the CD4-LCK than CD8-LCK interaction for proper T-cell responses. Subsequently, the development and immune response to viral and bacterial infections was almost normal in cytotoxic T cells in mice with disrupted LCK-coreceptor interactions. In contrast, the development and the immune reponse was largely impaired in helper T cells in the same mouse. We observed that the CD4-bound LCK has an important kinase-independent function by stabilizing the CD4 on the cell surface. The kinase-dependent role of CD8-and CD4-bound LCK is largely limited to the response to suboptimal antigens.It has been previously shown that the role of self-reactivity of naïve T cells is an important factor predicting their behavior during infections (Fulton et al.). Using a unique set of similar monoclonal T cells with a different level of self-reactivity, we addressed the role of self-reactivity in the development and immune response of mature peripheral T cells. We observed that highly self-reactive T cells form antigen-inexperienced memory-like T cells, but no a novel T cell subset with high expression of interferon type I-induced genes (Paprckova et al. 2022). Moreover, we did not observe any role of T-cell self-reactivity in the response of the T-cell clones during a bacterial infection.IL-17 is a crucial cytokine for the response to extracellular bacterial and fungal infections. However, it can also trigger autoimmune disorders, such as psoriasis. We have identified a novel component of the receptor for IL-17A and IL-17F (Knizkova et al.), a tetra-transmembrane protein CMMT4. Using the CRISPR-Cas9 approach, we generated CMTM4-deficient cell lines and mice. We have observed that the CMTM4 is required for the cellular and systemic response to IL-17 in terms of the activation of down-stream signaling pathways, cytokine production, neutrophile recruitment, and generation of autoimmune pathology in the model of experimental psoriasis.Regulatory T cells (Tregs) are crucial for maintaining the homeostasis of conventional T cells and for suppressing their over-responsiveness. We have focused on the mechanisms how Tregs suppress cytotoxic CD8+T cells. We have identified that the major mechanism is limiting the availability of IL-2, a key cytokine for the proliferation and survival of effector T cells (Tsyklauri et al. 2022). Surprisingly, the absence of Tregs and/or excess of IL-2 induces a formation of a previously unappreciated population of effector T cells expressing KLRK1, IL-7R, and lacking an established marker of effector T cells, CD49d (Figure 1). These KILR T cells show superior cytotoxic properties.Overall, we have uncovered some molecular mechanisms behind the homeostasis and immune response of T cells.

Název v anglickém jazyce

MOLECULAR MECHANISMS OF ADAPTIVE IMMUNITY AGAINST INFECTIONS

Popis výsledku anglicky

T cells are the major orchestrators of the adaptive immune responses against pathogenic bacteria and virus by inducing direct cytotoxicity (CD8+T cells) and by instructing the antibody production by B cells (CD4+T cells). On the other hand, the overt activation of the adaptive immunity leads to collateral damage to tissues and to the development of autoimmune diseases. Thus, the understanding of the molecular mechanisms of T-cell activation and regulation is crucial for desigining the therapeutic modulators of the immune response.LCK is a major protein tyrosine-kinase associated with the T-cell antigen receptor (TCR) triggering. It is bound to CD4 and CD8 co-receptors, which facilitate the TCR activation. We have generated novel mouse models to elucidate the role of CD8-LCK and CD4-LCK interaction. Surprisingly, we observed much greater importance of the CD4-LCK than CD8-LCK interaction for proper T-cell responses. Subsequently, the development and immune response to viral and bacterial infections was almost normal in cytotoxic T cells in mice with disrupted LCK-coreceptor interactions. In contrast, the development and the immune reponse was largely impaired in helper T cells in the same mouse. We observed that the CD4-bound LCK has an important kinase-independent function by stabilizing the CD4 on the cell surface. The kinase-dependent role of CD8-and CD4-bound LCK is largely limited to the response to suboptimal antigens.It has been previously shown that the role of self-reactivity of naïve T cells is an important factor predicting their behavior during infections (Fulton et al.). Using a unique set of similar monoclonal T cells with a different level of self-reactivity, we addressed the role of self-reactivity in the development and immune response of mature peripheral T cells. We observed that highly self-reactive T cells form antigen-inexperienced memory-like T cells, but no a novel T cell subset with high expression of interferon type I-induced genes (Paprckova et al. 2022). Moreover, we did not observe any role of T-cell self-reactivity in the response of the T-cell clones during a bacterial infection.IL-17 is a crucial cytokine for the response to extracellular bacterial and fungal infections. However, it can also trigger autoimmune disorders, such as psoriasis. We have identified a novel component of the receptor for IL-17A and IL-17F (Knizkova et al.), a tetra-transmembrane protein CMMT4. Using the CRISPR-Cas9 approach, we generated CMTM4-deficient cell lines and mice. We have observed that the CMTM4 is required for the cellular and systemic response to IL-17 in terms of the activation of down-stream signaling pathways, cytokine production, neutrophile recruitment, and generation of autoimmune pathology in the model of experimental psoriasis.Regulatory T cells (Tregs) are crucial for maintaining the homeostasis of conventional T cells and for suppressing their over-responsiveness. We have focused on the mechanisms how Tregs suppress cytotoxic CD8+T cells. We have identified that the major mechanism is limiting the availability of IL-2, a key cytokine for the proliferation and survival of effector T cells (Tsyklauri et al. 2022). Surprisingly, the absence of Tregs and/or excess of IL-2 induces a formation of a previously unappreciated population of effector T cells expressing KLRK1, IL-7R, and lacking an established marker of effector T cells, CD49d (Figure 1). These KILR T cells show superior cytotoxic properties.Overall, we have uncovered some molecular mechanisms behind the homeostasis and immune response of T cells.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30102 - Immunology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů