CD8+ T cells (TCD8) are a very important subset of T lymphocytes that participate in immune responses of adaptive nature to intracellular microorganisms (e.g., viral pathogens) and in immune surveillance against spontaneously arising neoplastic cells. On the other hand, harmful and undesired TCD8 activation is encountered in transplant rejection and in autoimmune disorders, in which grafted tissues and self components are seen as foreign by the immune system, respectively. Understanding TCD8 activation cascades and cellular and molecular mechanisms responsible for positive and negative modulation of TCD8 responses are therefore of prime importance. In clinical settings, consistent efforts are being made to boost TCD8 responses in infectious diseases and in cancer patients, whereas tolerizing autoreactive and alloreactive TCD8 is considered an ultimate goal in autoimmunity and organ transplantation, respectively.
TCD8 activation is initiated by professional antigen (Ag) presenting cells (pAPCs), particularly dendritic cells (DCs), which process and load 8-11-amino acid residue-long antigenic peptides onto their major histocompatibility complex (MHC) class I molecules for presentation to naïve TCD8 bearing a T cell receptor (TCR) of unique specificity. This highly specific interaction delivers “signal 1” to TCD8. Signal 1 is necessary but not sufficient for optimal T cell activation, which also requires a second or costimulatory signal provided by other molecular interactions between T cells and pAPCs. In fact, TCR triggering in the absence of appropriate costimulatory signaling may lead to a state of T cell unresponsiveness called anergy or even T cell death by apoptosis.
TCD8 are activated through direct priming or cross-priming. Direct priming of TCD8 occurs when endogenous Ags such as viruses propagating within the cytosol of a pAPC provide the substrate for Ag processing. However, many viruses avoid pAPCs or interfere with their endogenous pathway of Ag processing and presentation. Such viruses are typically dealt with by the exogenous pathway leading to TCD8 activation via cross-priming. Cross-priming refers to a process in which a pAPC acquires exogenous antigenic substrates from a donor cell (e.g., a virus-infected cell), which is not capable of priming naïve TCD8 on its own. Cross-priming is a robust phenomenon in development of TCD8 responses against viral pathogens, tumor cells and transplanted cells. It is noteworthy that DCs can also capture “pre-made” peptide:MHC complexes from other cells including dead or dying cells for presentation to TCD8. In this pathway, there is no need for further processing of the acquired complexes. The term “cross-dressing” has been coined to describe this phenomenon. “Cross-dressed” APCs have since been implicated in inducing TCD8 responses to tumor cells as well as to cancer vaccines.
A puzzling feature of TCD8 responses is immunodominance, which dictates that out of thousands of peptides harbored by complex Ags, only a selected few elicit measurable TCD8 responses of varying magnitude. This establishes a hierarchy among Ag-specific TCD8 clones. Accordingly, immunodominant epitopes provoke robust TCD8 responses, whereas subdominant epitopes activate TCD8 clones that occupy modest ranks in the hierarchy. The reason for immunodominance is unknown. Several factors are known to shape TCD8 hierarchies. These include the abundance of foreign gene products and the efficiency of their degradation by proteasomes, the rate and degenerate specificity of peptide transport into the endoplasmic reticulum (ER), the binding affinity of peptides for MHC class I molecules within the ER, and the existence of epitope-specific TCD8 within the host T cell repertoire. Our previous work has revealed a novel role for the template-independent DNA polymerase terminal deoxynucleotidyl transferase (TdT) in shaping TCD8 immunodominance. We also recently discovered that a serine-threonine protein kinase called the mammalian target of rapamycin (mTOR) moderates immunodominance disparities in mouse TCD8 responses against a clinically relevant tumor Ag called simian virus 40 (SV40) large T Ag.
Our research team investigates various aspects of TCD8 responses, including but not limited to cross-priming, immunodominance and cytotoxic effector functions in the context of infection with viral pathogens such as influenza A viruses and immune responses to tumor Ags (e.g., large T Ag).
Invariant natural killer T (iNKT) cells are rare but remarkably potent lymphocytes that link the innate and adaptive arms of immune responses. They are unique in several ways. First, they express an invariant T cell receptor (iTCR) that can unusually recognize glycolipid Ags in the context of the MHC class I-like molecule CD1d. Second, they contain messenger RNA for pro- and anti-inflammatory cytokines, typified by interferon (IFN)-γ and interleukin (IL)-4, respectively. As such, they can secrete large quantities of immunomodulatory cytokines early in the course of an immune response, thus shaping the nature of the ongoing or upcoming response.
Several scientists working in our lab are interested in various aspects of iNKT cell immunobiology, including their signaling pathways, costimulatory and coinhibitory requirements, interaction with other immunocytes and their potential therapeutic applications in various diseases. We were the first to identify the p38 MAP kinase as a negative regulator of iNKT cell responses, and glycosylphosphatidylinositol (GPI)-anchored proteins as non-classical costimulators of iNKT cells. In collaboration with Dr. John McCormick’s group at Western, we recently discovered that both mouse and human iNKT cells can be directly activated by group II bacterial superantigens (SAgs). We also reported the beneficial outcome of skewing iNKT cell responses towards a T helper (Th)-2-type phenotype in preventing cardiac allograft rejection and in citrulline-induced autoimmune arthritis.
The recognition of CD1d:glycolipid complexes by the iTCR is highly conserved throughout the mammalian evolution to the extent that mouse iTCR can recognize human CD1d and vice versa. In addition, prototype glycolipid agonists of mouse iNKT cells can also typically activate human iNKT cells. Therefore, findings obtained from mouse models are likely to be translatable to the clinic. In fact, iNKT cell glycolipid agonists have been employed and showed promise in several clinical trials for cancer and viral diseases.
Superantigens (SAgs) are microbial toxins that induce massive T cell activation and cytokine secretion in a non-specific manner. Despite intense investigation on these molecules, our understanding of how SAg-triggered responses are regulated by various components of the immune system and also by the very bacteria that produce SAgs is far from clear. We reported that T cell responses to the prototype staphylococcal SAg staphylococcal enterotoxin B (SEB) can be downregulated by the innate immunomodulatory protein lactoferin. We also recently identified iNKT cells as an important effector cell type responding to bacterial SAgs. Our team continues to investigate the biology of SAgs independently and also in collaboration with members of the Superantigen Interest Group at Western.
