One of the most interesting issues in immunology is how the innate and adaptive branches of the immune system cooperate in vertebrate organisms to respond and destroy invading microorganisms without destroying self-tissues. More than 20 years ago, Charlie Janeway proposed the innate immune recognition theory in which he hypothesized the existence of innate receptors (Pattern recognition receptors, PRRs) that, being expressed by antigen presenting cells (APCs) and epithelial cells, could alert the immune system to the presence of a pathogen, making it possible to mount an immediate inflammatory response. Moreover, by transducing the alert signal in professional APCs, these receptors would control the activation and differentiation of lymphocytes bearing clonal antigen-specific receptors, thereby promoting appropriate adaptive immune responses. Nowadays, this theory represents one of the most important rules of functioning of the immune system and a large part of the research in immunology is devoted to understanding the details of this principle.
Dendritic cells (DCs) have been identified as the cells of the innate immune system that, due to the expression of PRRs, are capable of interacting with microorganisms and transducing a signal to the nucleus (maturation process) that enables them to express signal 1 (specificity), 2 (activation) and 3 (differentiation) necessary for the priming of antigen-specific naïve T cell responses (signal 1 and 2) and T cell polarization (signal 3). What makes DCs superior with respect to other professional APCs in naïve T cell activation remains to be determined. It has not been established whether DCs can provide a special signal 2 (for instance IL-2 trans-presented via CD25) or, instead, very high levels, compared to other APCs, of commonly expressed signals 1 and 2; levels that allow a naïve T cell to reach the threshold of activation.
Concerning the question of how self-tissues are not destroyed following the initiation of adaptive immune responses, different mechanisms of central and peripheral auto-reactive T cell tolerization have been proposed. In particular, it has been defined that high affinity T cells are deleted in the thymus, while low affinity auto-reactive T cells or T cells specific for tissue-sequestered antigens that do not have access to the thymus are controlled in the periphery. In a simplified vision of how peripheral T cell tolerance could be induced and maintained, it was thought that, in resting conditions, immature DCs, expressing low levels of signal 1 and low or no levels of signal 2, were able to induce T cell unresponsiveness. Nevertheless, it is now clear that a fundamental contribution to the peripheral tolerance is due to the conversion of naïve T cells into regulatory T cells (iTreg cells) and it is also clear that DCs need to receive a specific conditioning to become able to induce iTreg cell differentiation. Even more intriguing is that also DCs activated through PRRs, with particular Toll like receptor (TLR) agonists, are capable of generating iTreg cell conversion if these agonists induce the production of the appropriate cytokines. Thus, what is emerging is that immature DCs are not able to induce tolerance by default but need to receive specific signals (and become alternatively activated) in order to acquire the ability of transferring to T cells what can be defined as a tolerogenic, rather than activatory, signal 2.
Given these premises, this Research Topic will cover a wide range of topics:
1. The responses induced specifically in DCs by PRR agonists and the consequences of these responses
2. The PRRs expressed by the different DC subsets and the consequences in terms of activation of adaptive immune responses
3
One of the most interesting issues in immunology is how the innate and adaptive branches of the immune system cooperate in vertebrate organisms to respond and destroy invading microorganisms without destroying self-tissues. More than 20 years ago, Charlie Janeway proposed the innate immune recognition theory in which he hypothesized the existence of innate receptors (Pattern recognition receptors, PRRs) that, being expressed by antigen presenting cells (APCs) and epithelial cells, could alert the immune system to the presence of a pathogen, making it possible to mount an immediate inflammatory response. Moreover, by transducing the alert signal in professional APCs, these receptors would control the activation and differentiation of lymphocytes bearing clonal antigen-specific receptors, thereby promoting appropriate adaptive immune responses. Nowadays, this theory represents one of the most important rules of functioning of the immune system and a large part of the research in immunology is devoted to understanding the details of this principle.
Dendritic cells (DCs) have been identified as the cells of the innate immune system that, due to the expression of PRRs, are capable of interacting with microorganisms and transducing a signal to the nucleus (maturation process) that enables them to express signal 1 (specificity), 2 (activation) and 3 (differentiation) necessary for the priming of antigen-specific naïve T cell responses (signal 1 and 2) and T cell polarization (signal 3). What makes DCs superior with respect to other professional APCs in naïve T cell activation remains to be determined. It has not been established whether DCs can provide a special signal 2 (for instance IL-2 trans-presented via CD25) or, instead, very high levels, compared to other APCs, of commonly expressed signals 1 and 2; levels that allow a naïve T cell to reach the threshold of activation.
Concerning the question of how self-tissues are not destroyed following the initiation of adaptive immune responses, different mechanisms of central and peripheral auto-reactive T cell tolerization have been proposed. In particular, it has been defined that high affinity T cells are deleted in the thymus, while low affinity auto-reactive T cells or T cells specific for tissue-sequestered antigens that do not have access to the thymus are controlled in the periphery. In a simplified vision of how peripheral T cell tolerance could be induced and maintained, it was thought that, in resting conditions, immature DCs, expressing low levels of signal 1 and low or no levels of signal 2, were able to induce T cell unresponsiveness. Nevertheless, it is now clear that a fundamental contribution to the peripheral tolerance is due to the conversion of naïve T cells into regulatory T cells (iTreg cells) and it is also clear that DCs need to receive a specific conditioning to become able to induce iTreg cell differentiation. Even more intriguing is that also DCs activated through PRRs, with particular Toll like receptor (TLR) agonists, are capable of generating iTreg cell conversion if these agonists induce the production of the appropriate cytokines. Thus, what is emerging is that immature DCs are not able to induce tolerance by default but need to receive specific signals (and become alternatively activated) in order to acquire the ability of transferring to T cells what can be defined as a tolerogenic, rather than activatory, signal 2.
Given these premises, this Research Topic will cover a wide range of topics:
1. The responses induced specifically in DCs by PRR agonists and the consequences of these responses
2. The PRRs expressed by the different DC subsets and the consequences in terms of activation of adaptive immune responses
3
