Immune Surveillance Inside Cells: Antigen Presentation, T Cells, B Cells, and Cancer Immunotherapy

Short Summary

This MIT OpenCourseWare lecture explores how the immune system detects intracellular infections through antigen presentation on MHC class I and II molecules. It explains how peptides derived from cytosolic proteins are loaded onto class I MHC and shown to CD8+ cytotoxic T cells, while extracellular or endocytosed proteins are processed for class II MHC and presented to CD4+ helper T cells. The talk covers the diversity of T cell receptors generated by VDJ recombination, the interaction between B cells and helper T cells, and mechanisms such as affinity maturation and isotype switching that enhance antibody responses. It also discusses how innate signals influence adaptive immunity, the balance between self and foreign recognition to prevent autoimmunity, and the Nobel Prize winning work on immune checkpoint blockade in cancer therapy, including potential autoimmune side effects.

Overview

The lecture uses an intracellular bacterium, listeria, to illustrate how the immune system detects infections that occur within a cell. It emphasizes antigen presentation as the key process that allows immune cells to observe peptides derived from intracellular pathogens, which would otherwise be hidden behind the host cell’s plasma membrane.

Antigen Presentation and MHC Molecules

The core concept is that peptides are displayed on the surface of cells by MHC molecules to be recognized by T cells. There are two main classes of MHC: Class I and Class II. Class I MHC is present on all nucleated cells and presents cytoplasmic peptides to CD8+ T cells, whereas Class II MHC is expressed on professional antigen presenting cells (APCs) such as B cells, dendritic cells, and certain phagocytes, and presents extracellular peptides to CD4+ T cells. The lecture describes the structural organization of these molecules and how they anchor peptides within a groove that faces outward to the extracellular space for T cell inspection.

Pathways for Class I and Class II Presentation

Class I loading begins in the endoplasmic reticulum where the MHC I heavy and light chains assemble. Cytosolic proteins (including unfolded or ubiquitinated ones) are degraded by the proteasome into peptides, which are then transported into the ER via the TAP transporter. There, they are loaded onto the MHC I molecule and trafficked to the plasma membrane for presentation to CD8+ T cells. Class II loading, by contrast, involves endocytosis of extracellular antigen into vesicles that fuse with lysosomes containing proteases. Peptides generated in this compartment are loaded onto Class II MHC and transported to the surface, where CD4+ T cells can recognize the peptide-MHC II complex. This difference in peptide source and loading location enables the immune system to sample different protein pools and tailor responses accordingly.

T Cells: Diversity and Co Receptors

The T cell receptor (TCR) recognizes peptide-MHC complexes. The TCR is composed of alpha and beta chains with variable regions that determine specificity. Diversity arises from VDJ recombination at the genomic DNA level, a process that creates irreversibly different receptors in progenitor cells, ensuring a vast repertoire capable of recognizing many different peptides. Co receptors CD4 and CD8 distinguish T cell subsets and their MHC targets: CD4+ T cells recognize Class II MHC, while CD8+ T cells recognize Class I MHC. This pairing ensures appropriate immune responses: helper T cells assist other immune cells, while cytotoxic T cells kill infected or malignant cells when they recognize foreign peptides presented by Class I MHC.

B Cells and T Helper Cells: Collaboration and Consequences

B cells internalize antigens via endocytosis, process them, and present peptides on Class II MHC to helper T cells. In response, helper T cells provide signals that drive affinity maturation, an somatic hypermutation process that increases antibody affinity for the antigen. They also induce isotype switching, changing the antibody class (for example from IgM to IgG, IgA, or IgE) to tailor effector functions, and promote differentiation into plasma cells and memory B cells. This B-T cell crosstalk is crucial for a robust, durable humoral response and for the development of vaccines that evoke both antibody and cellular immunity.

Innate Signals and Vaccine Design

The lecture highlights the role of innate immune signals as a coincidence detector: antigen recognition alone may be insufficient to trigger strong adaptive responses unless accompanied by innate immune activation, such as via adjuvants in vaccines. This ensures a robust and long-lasting response, which is essential for effective immunization strategies.

Self, Tolerance, and Autoimmunity

A central challenge for the immune system is discriminating self from nonself. Central tolerance in primary lymphoid organs (bone marrow for B cells and thymus for T cells) eliminates strongly self-reactive cells, while peripheral tolerance maintains tolerance to self in the periphery. Autoimmune diseases can arise when these mechanisms fail, as illustrated by conditions like myasthenia gravis, Type 1 diabetes, and multiple sclerosis. The lecture discusses real-world consequences of autoimmunity and the balance between broad immune surveillance and preventing self-reactivity.

Clinical Relevance: Cancer Immunotherapy

The Nobel Prize discussion centers on immune checkpoint blockade, particularly inhibitors of CTLA-4 and PD-1/PD-L1 pathways. James Allison and Tasuko Honjo demonstrated that blocking inhibitory receptors can unleash anti-tumor T cell responses, enabling immune recognition and killing of cancer cells. This therapeutic strategy can cause autoimmune side effects due to enhanced immune activity against self tissues, illustrating the delicate balance between effective cancer control and autoimmunity.

Takeaways

The lecture ties together how antigen presentation, TCR diversity, B cell collaboration, and innate signals collectively shape immunity. It emphasizes the distinct roles of Class I and Class II pathways, the importance of co receptors, the mechanisms behind antibody maturation and class switching, and the clinical implications for vaccines and cancer therapy.

Conclusion

Understanding these pathways clarifies how the immune system detects and fights intracellular pathogens while maintaining tolerance to self, and how modern therapies harness these pathways to treat disease while acknowledging potential risks.