Co-stimulation- Nature's Safety Catch

Why don't the immune cells in our body run amok and attack our own tissues? Well, sometimes they do, resulting in autoimmune diseases like type I diabetes mellitus, pernicious anaemia, vitiligo, etc, but mostly they are kept in check.

The way this happens is through an elaborate system of checks and balances. The first of these occur in the thymus- the site of development and maturation of T cells, where they migrate soon after they are formed in the bone marrow.

In the thymus, young T cells come in contact with the body's own antigens- called "self antigens"- on the natural residents of the thymus- the epithelial & stromal cells. These antigens are recognised when they are "presented" to the maturing T cells, gift-wrapped in MHC molecules- also known as HLA, the major determinants of transplant success in allogenic transplants. T cells that recognise these MHC-self antigen complexes are selected to survive- a process called positive selection.

However, the thymus does not contain many antigens, which are sequestered in far-flung tissues of the body- the pancreatic antigens, for example. When the mature T cells are released into the circulation, there is a real danger that these would then attack the body's own tissues, mistakenly interpreting the hitherto hidden self antigens as foreign.

Why doesn't this happen?

This is because of need for co-stimulation. The mature T cell with its receptor bound to hitherto unfamiliar antigens carried on self MHC proteins is like a loaded gun....but with its safety-catch on. Co-stimulation is that safety catch.

I had alluded earlier to the fact that for T cells to recognise antigens, these must be carried in the groove of self MHC molecules. These molecules are in turn part of specialised cells called antigen presenting cells (APC).

When APCs, carrying the self MHC molecule, holding the antigen in its embrace, meets and binds to a T cell receptor, the T cell asks- "Is that all you have got for me? Where's your co-stimulation molecule?"

Every mature T cell constitutively expresses a marker called CD28. The ligand (something that it ligates) for this is something called B-7, present on APCs. There are two types of B7- B7-1 (also called CD80), and B7-2 (also called CD86). Only when a CD28 on T-cell binds to a B7 on an APC does the T cell become activated. Since this is required in addition to the T cell receptor recognising the putative (foreign) antigen bound to a self MHC molecule in the APC, the process is called co-stimulation.

The nice bit is that co-stimulation molecules on APC- B7- does not become expressed until the APC meets an invading pathogen. These pathogens have certain patterns- lipopolysaccharides on gram negative bacteria, for example- that are called pathogen associated molecular patterns or PAMPs. The PAMPs bind to certain probes on APCs that recognise them- called pattern recognition receptors or PRRs. The most well known PRRs are a group of primitive receptors called Toll-like receptors (TLR), characterised only recently from fruit flies.

Thus when the TLR or a similar PRR on the APC recognises a PAMP on an invading pathogen, B7 becomes expressed on the APC. The APC is now "licensed" to activate a mature T cell. The safety catch is off.

This principle has been exploited in medicine through a drug called Abatacept, used successfully in the treatment of Rheumatoid arthritis. Further attempts at exploiting the phenomenon backfired when volunteers at a drug trial in London became critically unwell after administration of an experimental drug. More on that soon.