Research: T cell receptor types in MS.


Analysis of the paired i.e. matching TCR α- and β-chain rearrangements of single human T cells is required for a precise investigation of clonal diversity, tissue distribution and specificity of protective and pathologic T-cell mediated immune responses. 

Here we describe a multiplex RT-PCR (reverse transcription polymerase chain reaction. So this starts with RNA and then you convert this to DNA before amplifying this with PCR. This gives an indication about what proteins are being made) based technology, which for the first time allows for an unbiased analysis of the complete sequences of both α- and β-chains of TCR from single T cells. We validated our technology by the analysis of the pathologic T-cell infiltrates from tissue lesions of two T-cell mediated autoimmune diseases, psoriasis vulgaris (PV) and multiple sclerosis (MS). In both disorders we could detect various T cell clones as defined by multiple T cells with identical α- and β-chain rearrangements distributed across the tissue lesions. In PV, single cell TCR analysis of lesional T cells identified clonal CD8(+) T cell expansions that predominated in the epidermis of psoriatic plaques. An MS brain lesion contained two dominant CD8(+) T-cell clones that extended over the white and grey matter and meninges. In both diseases several clonally expanded T cells carried dual TCRs composed of one Vβ and two different Vα-chain rearrangements. These results show that our technology is an efficient instrument to analyse αβ-T cell responses with single cell resolution in man. It should facilitate essential new insights into the mechanisms of protective and pathologic immunity in many human T-cell mediated conditions and allow for resurrecting functional TCRs from any αβ-T cell of choice that can be used for investigating their specificity
We have posted on the structure of the T cell receptor and what it does.  Each set of alpha and beta chain genes of the receptors shape the receptors that can bind to their targets. If they are all the same they may be clonal (i.e. a clone. The cells are the progeny from a single cell that has multiplied=divided to make lots of the same cells. This is clonal expansion. When you see evidence of clonal expansion, this suggests that they are involved or are triggered by the disease process. In this study they looked for the sequence of the T cell receptors from cells that had activation markers suggestive of effector cell function.
If you have to select the way that you the response when it is measured, you can bias or skew the results obtained. This report shows a way that the array of immune responses can be probed in a seemly unbiased way. This report showed that the cells had one beta chain and two alpha chains. We have heard of this before. Normally only one alpha and beta are
present and can recognise one target if there is an extra alpha chain then it
could recognise a different target. So by having
more than one set of T cell receptors such as one that is viral-specific, and one say to a nerve proteins. Activation of the cells say to a virus (which the cells react to) could cross-react with a nerve protein. This is a  form of molecular mimicr.

concept whereby cells have dual (two) T cell receptors has been
demonstrated many years ago, particularly with cells containing extra
alpha chains in the context of of other viral infection or autoimmune
conditions. This is yet another way that autoimmunity could develop
following viral infection.

The problem is that this technology does not give us the identity of what the T cell receptors are reacting to. Further work will be needed to express these T cell receptors and then  hunt to find out what the target is. Then this may be more interesting and will help us find the autoantigen or viral, bacterial target..if there is one.

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