Periodic Reporting for period 4 - STEP 2 (Spatiotemporal regulation of T-cell Priming)
Período documentado: 2024-03-01 hasta 2025-04-30
The initiation of an adaptive immune response is orchestrated within secondary lymphoid organs such as lymph nodes and the spleen. Here, diverse immune cell types converge, exchange information, and activate one another in a highly coordinated manner. The central task of the immune system is to mount a rapid, effective, and highly specific response to eliminate invading pathogens. Among the key players are cytotoxic CD8 T cells, which are indispensable for controlling intracellular infections and, importantly, for combating cancer. Strategies that reinvigorate CD8 T cell activity—such as checkpoint immunotherapy—have transformed cancer treatment. Thus, understanding how these cells are optimally induced and activated remains a matter of prime importance.
The challenge of orchestrating such a multifaceted immune response, requiring precise cooperation between specialized cell types, is strikingly similar to the dynamics of teamwork. Just as individuals with diverse expertise must communicate, collaborate, and align toward a shared goal, immune cells must interact efficiently to generate a coordinated defense. Traditionally, research has focused on identifying the core cellular players (the “team members”) involved in initiating effective immune responses against different classes of pathogens.
In this proposal, we aim to move beyond identifying the players to explore the novel mechanisms, specific contexts (microenvironments), and regulatory elements that shape immune cell interactions. Our first aim is to uncover previously unrecognized modes of intercellular communication. In the teamwork analogy, this corresponds to understanding how team members remain focused on the common goal and whether unexpected channels of communication (e.g. “social media”) play critical roles in achieving success.
Our second aim is to investigate how distinct microenvironments—defined by local cytokines and other inflammatory cues—govern immune cell interactions and influence the overall quality of the immune response. In other words, does the effectiveness of the “team” depend on the meeting environment—whether a formal conference room, a casual coffee shop, or an outdoor setting—and are certain regulatory elements active only in specific contexts?
Finally, we seek to elucidate the regulatory circuits and feedback mechanisms that fine-tune immune responses. Do some environments or niches amplify inhibitory feedback, thereby limiting the effectiveness of the team? By understanding these principles, we will gain insight into how immune cells work together to generate protective responses—or, conversely, how miscommunication can lead to pathology.
Ultimately, dissecting how immune cells cooperate as a team will provide the foundation to manipulate these interactions therapeutically. This knowledge is essential for enhancing immune responses against infections and cancer, as well as for suppressing harmful immune activity in autoimmune diseases. By uncovering these fundamental principles, we hope to open new avenues for targeted therapeutic interventions, with particular promise for improving cancer immunotherapy.
The challenge of orchestrating such a multifaceted immune response, requiring precise cooperation between specialized cell types, is strikingly similar to the dynamics of teamwork. Just as individuals with diverse expertise must communicate, collaborate, and align toward a shared goal, immune cells must interact efficiently to generate a coordinated defense. Traditionally, research has focused on identifying the core cellular players (the “team members”) involved in initiating effective immune responses against different classes of pathogens.
In this proposal, we aim to move beyond identifying the players to explore the novel mechanisms, specific contexts (microenvironments), and regulatory elements that shape immune cell interactions. Our first aim is to uncover previously unrecognized modes of intercellular communication. In the teamwork analogy, this corresponds to understanding how team members remain focused on the common goal and whether unexpected channels of communication (e.g. “social media”) play critical roles in achieving success.
Our second aim is to investigate how distinct microenvironments—defined by local cytokines and other inflammatory cues—govern immune cell interactions and influence the overall quality of the immune response. In other words, does the effectiveness of the “team” depend on the meeting environment—whether a formal conference room, a casual coffee shop, or an outdoor setting—and are certain regulatory elements active only in specific contexts?
Finally, we seek to elucidate the regulatory circuits and feedback mechanisms that fine-tune immune responses. Do some environments or niches amplify inhibitory feedback, thereby limiting the effectiveness of the team? By understanding these principles, we will gain insight into how immune cells work together to generate protective responses—or, conversely, how miscommunication can lead to pathology.
Ultimately, dissecting how immune cells cooperate as a team will provide the foundation to manipulate these interactions therapeutically. This knowledge is essential for enhancing immune responses against infections and cancer, as well as for suppressing harmful immune activity in autoimmune diseases. By uncovering these fundamental principles, we hope to open new avenues for targeted therapeutic interventions, with particular promise for improving cancer immunotherapy.
During this project, we developed new technical approaches and experimental models to investigate how, where, and when different immune cell types interact to generate a fully functional cytotoxic CD8 T cell response. In particular, we established an intravital microscopy approach that enabled imaging of deeper regions of the lymph node. This allowed us to visualize critical cellular interactions that had not been accessible before, leading to the discovery of a previously unrecognized second phase of CD8 T cell activation.
This second phase occurs within a specialized microenvironment – the so-called subfollicular niche –where key immune cell types physically interact. We found that CD4 regulatory T cells, CD4 helper T cells, and cytotoxic CD8 T cells each displayed distinct migratory behaviors within this niche. Regulatory T cells were highly motile and scavenged the cytokine IL-2, which was secreted by helper T cells as they migrated in a characteristic stop-and-go pattern. In turn, IL-2 was locally provided to fully arrested CD8 T cells, thereby driving their differentiation and proliferation.
These fundamental insights shed light on how complex cellular interactions are orchestrated. Importantly, our findings have direct implications for the design of immunotherapies and vaccines, as they reveal when and where signals such as IL-2 must be delivered to optimize CD8 T cell responses.
This second phase occurs within a specialized microenvironment – the so-called subfollicular niche –where key immune cell types physically interact. We found that CD4 regulatory T cells, CD4 helper T cells, and cytotoxic CD8 T cells each displayed distinct migratory behaviors within this niche. Regulatory T cells were highly motile and scavenged the cytokine IL-2, which was secreted by helper T cells as they migrated in a characteristic stop-and-go pattern. In turn, IL-2 was locally provided to fully arrested CD8 T cells, thereby driving their differentiation and proliferation.
These fundamental insights shed light on how complex cellular interactions are orchestrated. Importantly, our findings have direct implications for the design of immunotherapies and vaccines, as they reveal when and where signals such as IL-2 must be delivered to optimize CD8 T cell responses.
The question of how, when, and where CD4 T cells provide helper signals to cytotoxic CD8 T cells has been debated since the principle was first described more than 40 years ago. A major limitation of earlier studies was the experimental depletion of all CD4 T cells – removing both helper and regulatory subsets – rather than selectively targeting CD4 helper T cells to assess their specific function. We overcame this challenge and, in doing so, not only demonstrated the pivotal role of helper T cells during the primary antiviral immune responses, but also uncovered the spatiotemporal principles by which they support CD8 T cell activation and differentiation.
This breakthrough represents a significant advance beyond the state of the art, resolving a long-standing question in the field. Importantly, clarifying the mechanisms of CD4-CD8 T cell cooperativity is of prime relevance given its critical role in cancer immunity and the development of effective cancer immunotherapies.
This breakthrough represents a significant advance beyond the state of the art, resolving a long-standing question in the field. Importantly, clarifying the mechanisms of CD4-CD8 T cell cooperativity is of prime relevance given its critical role in cancer immunity and the development of effective cancer immunotherapies.