Cross presentation: presenting unexpected antigens to the cell-mediated immune response.

Please cast your minds back to basic immunology. I am sure you remember there is the innate immune response (boring) and the acquired/adaptive immune response (very interesting). Perhaps the most interesting part of it is the gene re-arrangement to generate antibodies and T cell receptors (TCRs). But this re-arrangement is random; how can they tell self from non-self? The very basic explanation is seems to be that antigen (Ag) presenting cells (APCs) shows lymphocytes these Ag in the local draining lymph nodes when the body knows it is ill (ie the innate immune system is acting up). (Sorry for this long introduction to the topic but I need to remind myself of this while I type on the train myself.)

A problem comes when we remember a bit of basic immunology. Peptide Ag presented on MHC class II molecules to CD4+ T cells (T helper cells) are taken up by APCs and are exogenous Ag. However, peptides shown on MHC class I to CD8+ T cells are generated from endogenous proteins. So how can a virus that infects only the liver like hepatitis or the respiratory system (like rhinovirus or flu) show their peptide Ag to naive CD8+ T cells (cytotoxic T cells or CTLs for short) which live in the lymph organs. Unless all viruses also affect the APCs as well then it seems impossible! Let’s forget how ridicules that idea is first and remember CTLs also attack tumour cells expressing mutant proteins. Cross presentation appears to be the answer. Somehow, APCs such as dendritic cells (DC) take up proteins from other cells and process these in a manner that means they are treated like endogenous proteins and therefore processed to be peptide Ag loaded onto MHC class I. This is called cross presentation, when CTLs are activated this way they are cross primed. The fine details of this appear to be missing but a lot of evidence is mounting that shows this must be the case. Other than this I can see no other way apart from the naive CTLs circulating the body and activating their; but no evidence has been found for this that I can see (I am pretty sure this also flies in the face of most accepted ideas in immunology). There are four ways for DC to capture extracellular proteins; (i) endocytosis (ii) pinocytosis (cell drinking) (iii) phagocytosis and (iv) macropinocytosis. For example, phagocytosis can be the uptake of a bacterium or cellular debris such as an apoptotic body. When cells are signalled to undergo apoptosis the dying cell starts to bleb and releases intact fragments of the cell called apoptotic bodies that express ‘eat-me’ signals. It is not a huge leap of the imagination to think this could be a major way tumour proteins are presented to naive CTLs.

So how do these exogenous proteins within sub-cellular compartments such as the endosome or phagosome get loaded onto the MHC class I molecules? It is a good question and various routes have been suggested and evidence for some of these have been found. In DC exogenous proteins have been shown to be exported into the cytosol before they are degraded in the lysosome. This means they can be substrate for the proteasome and broken down to short peptides to be exported across the ER membrane by TAP. When here they can bind to the peptide binding cleft of MHC class I molecules and move to the cell surface like normal endogenous proteins in the classical presentation pathway. Another pathway acts in the endosome. This TAP/proteasome independent pathway uses cathepsin S to generate some peptide Ag. It is unclear whether other peptides here also act but currently appears unlikely. What I find amazing is how this protease produces peptides of the correct size of 8 or 9 amino acids residues long to load onto MHC class I molecules. This pathway even produces the same peptide Ag as the much more complex proteasome based pathway. When both pathways are knocked out most of the cross-presentation in vivo is lost.
Interestingly, tolerance to an Ag can be generated using these mechanisms when no stimulator of the immune system is present, and this has been called cross tolerance. It is now clear cross presentation is not some strange phenomenon like originally thought when discovered but is a key part of the immune system. When you knockout these pathways for cross-presentation none occurs. The next step is to manipulate this with vaccines to stimulate the cell-mediated immune response. Often only antibodies are produced because the antigens are not cross-presented.

A short and sweet review:
Brode and Macary (2004) Cross-presentation: dendritic cells and macrophages bite off more than they can chew!

A full and great review:
Rock and Shen (2005) Cross-presentation: underlying mechanisms and role in immune surveillance.

Colds and the cold

My mum always told me if I didn’t wear socks and shoes and had cold feet I would get a cold! Some evidence suggests that this old wives tale may be true. Adults have about 3-5 cold infections every year (unless you are a student and it is considerably more than this) and the symptoms are so well know and easily recognised that people self diagnose and there are no special tests doctors perform to say you have a cold, they go off these same old symptoms as the public. Saying what is a cold or flu is not easy but flu is much worse than most common colds, but a bad cold could be easily confused with a mild case of flu. Someone’s reaction to an upper respiratory infection depends more on the person (such as there stress level) than the virus that infects them. There are more than 200 serotypes of viruses (viruses with different antigens) that cause the common cold. Once infected by one of them you have antibodies to protect you from it causing another cold but there are plenty more waiting in the wings to hit you the next time exams are approaching. The rhinovirus is the most common cause of the common cold. The symptoms we experience when we get a cold are not the virus damaging us but our body reacting to the virus. Histamine triggers nerves in the noise to fire and tell the brain to make you sneeze and a sore throat is from a small peptide (bradykinin) signalling to nerves to tell you something is wrong. The colour of you lovely mucus changes from clear to yellow to green as more leukocytes (such as neutrophils) are recruited to fight the infection (Eccles, 2005). The majority of infected people are believed to not have any symptoms or only very mild ones. These are called cub-clinical infections and they can spread to others who will develop a full blown cold (Eccles, 2002).

The question is does the cooling of the body’s surfaces increase the chances of you getting a cold. The name cold suggests a link to me. The usual answer to why we get more colds in winter and cold weather is because we all crowd around in close spaces indoors and breath the same air. However I disagree with this. I do not change my habits during the winter and summer, I live in the same house with the same people who stay in the same no matter what the weather and go to school/uni and sit in the same classes with the same amount of people no matter what the weather. So how can you explain why I get more colds in the winter? I guess my mum is right. Because my feet aren’t warm enough…well there is now evidence to support my mum’s theory. Eccles and Johnson (2005) did find that when people put there feet into cold water and were exposed to a virus they were more likely to develop cold symptoms than those who did not have cold feet. But what are the mechanisms that mean cooling of the body’s extremities to let the virus get the upper hand? Vasoconstriction happens when you get cold, therefore less blood flows to the upper airways. This restricts the supply of heat and nutrients to leukocytes that eliminate viruses in a non-specific manor and reduces phagocytosis. Virus replication may also be increased, rhinoviruses replicate better at 33^oC than 37^oC. This could all cause a sub-clinical infection to become a full blow cold! Runny noise and all. Vasoconstriction helping cause a cold may also explain why some people get more colds than others. It has been shown that people who get more colds a year have a greater vasoconstriction response than those who only get a couple of colds per year (Eccles, 2002).

There are a lot of questions about colds and how they cause disease and how we catch them. But these diseases do not cause a lot of deaths, only reduce work output and the symptoms can be treated directly. I am just interested in what happens when I am ill.