Cell-Mediated Immunity II

Part II! Click here for part I.

Describe interactions of T-cells during Cell-Mediated Immunity (CMI)
Describe types and effector functions of CMI

I feel like I've pretty much already done this, but okay then. Cytotoxic T-lymphocyte recognises an antigen bound to MHC, gets activated, releases toxic stuff, infected cell dies. The end.

Another way in which cytotoxic T-cells kill stuff is via the FasL/Fas pathway. Activated CD8 T-cells express FasL (Fas ligand), which binds to Fas (a.k.a. CD95) on target cells. This triggers apoptosis in the target.

There's not really much else to say here aside from an overview of T-cell activation and a note on how MHC restriction (i.e. the ability of cytotoxic T-cells to only bind to certain MHC molecules) was discovered.

Overview of T-cell activation

Professional antigen-presenting cell meets antigen and takes it to a secondary lymphoid organ (e.g. lymph node), where it shows off its cargo to a T-cell. T-cell expands and differentiates and it (and its clones) enter circulation. T-cells then encounter antigens and either kill stuff (cytotoxic T-cells) or release cytokines (helper T-cells). And then everyone lived happily ever after.

Discovery of MHC restriction

MHC restriction was discovered by Zinkernagel and Doherty, who received a Nobel Prize for their work. Essentially they got a mouse, immunised it against a virus and harvested the lymphocytes. Then they got some virus-infected cells and labelled them with radioactive chromium. Essentially, if the lymphocyte recognised the virus-infected cell, it would kill it, causing the cell to lyse and release radioactive chromium. Chromium levels were then measured to determine the amount of cell lysis.

Basically, what they found was that in order for cell lysis to occur, the H-2 haplotype of the cell had to be the same as the H-2 haplotype of the mouse (see here if you've forgotten all about haplotypes) and the virus that the cell was infected with had to be the same as the virus that the mouse was immunised against. That indicated that both the type of MHC molecule and the peptide bound were important.

Describe functions of macrophages in CMI

Macrophages are also cells that can kill things, so they count as also being part of CMI. Macrophages have a range of receptors on their cell surfaces that bind antigens found on many microbes, such as mannose, glucan (a part of fungal cell walls) and certain lipids. They also have receptors for complement, allowing them to take up opsonised antigens.

You should hopefully know by now that macrophages are heavily involved in phagocytosis (after all, "macrophage" literally means "big eat"). After a microbe binds to one of the receptors on the macrophage surface, it is taken up by phagocytosis. The resulting phagosome then fuses with a lysosome to form a phagolysosome, where the pathogen is degraded.

The degradation of pathogens occurs via several mechanisms. There are some enzymes produced in phagolysosomes that degrade pathogens directly, such as elastase. NO (nitric oxide), which is toxic to many pathogens, is produced by the enzyme iNOS (inducible nitric oxide synthase). Reactive oxygen intermediates (ROIs), which are also toxic, are produced by another enzyme called phagocyte oxidase. In chronic granulomatous disease, there is a mutation in phagocyte oxidase, making pathogen killing much less efficient.

Macrophages can kill stuff quite happily on their own, but once activated by a T_H1 cell, they can become extra potent killing machines. When CD40L on the T-cell binds with CD40 on the macrophage, and IFN-γ produed by the T-cell binds to IFN-γ receptors on the macrophage, the macrophage becomes activated. When activated, the macrophage increases expression of several cell surface molecules, including MHC-II, TNF receptors, B7 and CD40 receptors. They also become more efficient at producing NO and begin to secrete TNF-α and IL-12. TNF-α acts in an autocrine fashion on macrophage TNF receptors, thus providing positive feedback to the macrophage. IL-12 acts on T-cells in the vicinity to upregulate STAT4, resulting in more development of T_H1 and thus even more positive feedback.

Describe natural killer (NK) cells

NK cells are some of the earliest responders to an infection. They are activated by type I interferons (IFN-α and IFN-β) and macrophage-derived cytokines. In return, they can produce IFN-γ (type II interferon) to help activate T-cells.

Just like macrophages, NK cells have receptors that can recognise a variety of peptides. They also have a way of responding to the amount of MHC molecules present on the cell surface. NK cells have KIRs (killer inhibitory receptors) on their cell surface, which bind to MHC molecules and inhibit killing. If MHC is down-regulated, however, as sometimes happens in viral infection, the KIRs do not bind and the lack of inhibition causes the NK cell to kill the infected cell. For the infected cell, it's kinda like a "damned if you do, damned if you don't" situation: if they down-regulate MHC, they get killed by NK cells; if they don't down-regulate MHC, they get killed by cytotoxic T-cells.

Another way in which NK cells can act is via ADCC (antibody-dependent cell-mediated cytotoxicity), which I have described in an earlier post, so I'm not going to describe it again. The mechanism of killing is somewhat similar to that of cytotoxic T-cells, with perforins and all that.

Next Monday is the second midterm- good luck!