Published Stories from the lab
Narrative details of previously published stories from the lab
Team Time
A focus on structure
Immune responses benefit from organization. Secondary lymphoid tissues (SLOs) provide this by both recruiting adaptive and innate immune cells and facilitating their interactions. This allows for the initiation of T cell responses, but also for the maintenance of T cell populations through the provisions of critical cytokines, like IL-7. By contrast, it is the disruption of the normal architecture that is thought to impair immune responses against chronic viral infections such as Clone 13 LCMV infection.
In peripheral tissues, tertiary lymphoid structures (TLS) are thought to serve many of the same putative functions
as SLOs, but less is known about these structures. Recent work has highlighted that TLS are frequently associated with cancer across many types, and their presence correlates with better outcomes and responses to immunotherapy. However, what theses structures do remains unclear.
Team tolerance
PD-1: Preventing T cell pathogenesis
“The crux of the study … is the identification of a form of peripheral T cell tolerance that is distinct from the dominant mechanisms of clonal deletion and anergy that operate during T cell priming.”
CD8 T cells develop a T cell receptor (TCR) in the thymus that has the ability to both recognize the major histocompatibility complex 1 (MHC-I; also known as HLA) protein and the peptide contained within that molecule (antigen). CD8 T cells undergo deletion for binding of the MHC (positive section) and absence of recognition of self-antigens (negative selection) in the thymus, but this is an imperfect process.
Studies in humans have found that self-antigen reactive T cells are present in circulation, but it is thought that these cells have been inactivated by mechanisms of peripheral tolerance. Previous work has focused on the role of two processes: Anergy and Deletion in preventing autoimmunity from self-reactive CD8 T cells, which should result in irreversible silencing and protection from disease. This included a putative role for PD-1 in promoting T cell tolerance via anergy.
The advent of immune checkpoint blocking therapies revealed the common occurrence of immune related adverse events, which are autoimmune like events that are thought to be mediated by self-reactive T cells. Yet this raised the question of why these self-reactive T cells were not previously anergized or deleted, which led us to re-examine the mechanisms for peripheral tolerance in skin using our NINJA model.
TEAM TIME
Keeping some T cells in reserve
CD8 T cell responses are dynamic processes that are regulated by the signals that T cells receive from their environment. In the context of acute responses, these signals are delivered around the time of initial priming by the dendritic cell, but in chronic responses like cancer, T cells continue to receive signals from their environment and this can drive their terminal differentiation. One critical signal for this is the signal from antigen, which both drives proliferation and differentiation. Unfortunately for the host, unchecked proliferation and function of T cells can lead to lethal immunopathology, so T cell responses are highly regulated through both the expression of inhibitory “checkpoint” receptors on T cells and by the trade-off of proliferative capacity for effector function & migration into tissues that accompanies terminal differentiation. These mechanisms largely prevent lethal immunopathology, but can hinder potentially effective response against cancer.
Not all T cells are thought to reach the terminal effector stage in an immune response. Indeed, in most cases, a subset of less-differentiated stem-like T cells can be identified that retain high proliferative and functional capacity. These T cells are often quiescent, likely due to the need to protect these cells signals that would promote their terminal differentiation. Absent this protection, the entire antigen-specific CD8 T cell pool could become terminally differentiated, which would yield a “hole” in the T cell repertoire that future pathogens could exploit. This phenomenon is observed in extreme cases of chronic infection (e.g., CD4-deficient Clone 13 infected mice), but remains poorly understood. Given the potential for chronic antigen exposure to “exhaust” entire populations of antigen-specific CD8 T cells, we wondered how T cell responses are sustained in the tumor microenvironment, which contains high amounts of these differentiation-promoting signals.
A PROBLEM OF LEAKINESS
Developing thymocytes are very sensitive to the presence of their cognate antigen. As they transit through the medulla, thymocytes are exposed to many self antigens and the consequences of binding between the TCR and these self antigens can result in clonal deletion or development into a regulatory T cell fate (central tolerance). This process prevents autoimmunity, but is a challenge for the development of animal models where the goal is to have inducible neoantigens in the periphery. This is because any leakiness will result in central tolerance and it has traditionally been challenging to regulate antigen in a manner that prevents leaky expression in the thymus.
ENGINEERING A NEOANTIGEN
To tackle this engineering problem, we recognized that the neoantigen would need to be generated through the process of induction in the periphery. However, this would require both recombination based regulation and a means to encode the neoantigen in a manner that would produce proteins that were not affected by this machinery.
