Immunogenetics class 3: T cell gene rearrangement

What is T cell receptor and How T cell receptor diversity is generated?

What is MHC molecule and How different gene segment for MHC is arranged?

 

Image credit: Wesley Bedrosian/theispot

 

As like B cells, T cells are also a significant cell type of immune system. Same as B cells, Even, T cell produces surface receptors which recognize a wide range of antigens. These cell receptors are almost similar to B cell antibody. But one question strikes in mind regarding the function of T cell is, how T cell avoids the duplication of function with B cells?

Well, T cell recognizes both the antigen and the surface receptor. This secondary cell surface protein receptor which must be recognized by T cell is called as MHC, Major Histocompatibility Complex.

MHC locus encodes a great diversity of protein receptors and it functionally destroys both internal and external antigens. When any of our cells produce antigen, it is recognized by MHC molecules and the complex is further processed for lysis of antigen.

Structurally, the T cell receptors are made up of alpha and beta chain and as like antibody, it is made up of L, V, D, J and C gene segments. Both alpha and beta chain has a variable region which is a binding site for antigen.

Structure of T cell receptor
The figure represents the general structure of T cell receptor which is embedded into the cell membrane, compared with different gene segments of T cell receptor

Variability is provided by the arrangement of V-D-J gene segments during the differentiation of T cells. Constant regions are encoded by C gene segments which helps receptor to embedded into the cell membrane.

Alpha and beta receptor genes are clustered on chromosome number 14 and 7 respectively. The gene segment rearrangement is similar to antibody gene segments. Furthermore, heptamers and nonamers again perform a crucial role in alpha and beta chain gene rearrangement.


Read related article: Immunogenetics class 1


Though the mechanism is almost the same in both types of cells, the numbers of polypeptide chains differ in both. For example, T cell receptors variable region are encoded by 30 V gene segments, whereas there are about 300 Variable gene segments are present for B cell antigen.

The multigenic MHC protein complex (all cell surface receptors are protein,  for more detail, read the article story of protein ) is encoded by HLA locus, human leucocyte antigen locus on chromosome 6. A large number of genes are present on this locus which gives diversity to T cell MHCs. The number of the allele are so diverse that the chance of similarity between two individual for one particular HLA, is very less. It is a highly polymorphic region.

Further, these MHC (HLA) locus are classified into three different classes. Majorly class 1 MHC genes encode polypeptides that are responsible for rejection of foreign tissue during organ transplantation. Class 1 antigen are called as the transplantation antigen.

Class 2 MHC genes encode polypeptides that are located on macrophages and B lymphocytes, whereas class 3 MHC gene segments are encoded into complement protein.

During organ transplantation or bone marrow transplantation, HLA typing plays a crucial role. If both, donor and recipient’s HLA typing is not matched, graft rejection leads to failure in transplantation, and the individual may die.

Here different locus of HLA, (however there are millions of alleles for HLA, we cannot match all the alleles) locus are matched with the recipient and if it will 100% matches, the graft can be implanted.

HLA class1: HLA A, HLA B, HLA C,

HLA class 2: HLA DRB1, HLA DRB3, HLA DRB4, HLA DRB5, HLA DQR1

Enlisted loci are majorly used in HLA-DNA typing routinely. Multiple alleles which means that if you take a single HLA A antigen locus, there may be multiple alleles are present, all this allele must be in an exact match with the recipient, and this criterion is for all HLA antigen listed above.

As shown in the figure, all the HLA markers are matched between donor and recipient. hence the donor can donate organ or bone marrow to the recipient.

For low resolution typing simple PCR based gel electrophoresis is sufficient for analysis. Locus-specific universal primers are used, PCR amplicons are compared on gel electrophoresis. It is simple and effective and only 4 to 5 HLAs are necessary for analysis.

In high-resolution HLA typing, next-generation sequencing and microarray-based analysis give the best result. However, as compared to low-resolution analysis NGS based high-resolution analysis gives the best result along with sequence comparison with expression of that particular alleles.

In case of thalassemia major and sickle cell disease, bone marrow transplantation gives hope to the patient. In that case, HLA typing is a very important tool for matching donor’s and recipient’s compatibility.


Read related articles: Immunogenetics class 2


It is one possibility that one of your family members has the same HLA pattern as yours but it is not happening in all cases. Universal donor registry now becomes more popular where you can register your donor status and you can donate organ or bone marrow to other persons.

As shown in the figure, DRB3 and DQR1 markers are mismatched between donor and recipient. hence the donor cannot donate organ or bone marrow to the recipient.

However, it is possible that graft may reject in one out of a thousand cases because how the immune system reacts in different conditions is still one question for modern science. Living with the foreign organ is not as easy as a normal person because immune system reacts adversely, immune suppressors are given to patients for some time until the organ is not fully accepted by the recipient’s body.

During this period chance of infection with life-threatening diseases are greater. The patient can be infected with TB, HIV or HCV like infections and even we cannot save them because their immune response becomes so poor, due to the immune suppressor.

One of my friends is living with a transplanted kidney for the last 5 years but his condition is still very sensitive, he easily becomes ill during seasonal changes. Additionally, one of their member ( from their donor society) died last year even though he was absolutely fine.

We can understand that the chance of survival even after graft acceptance is uncertain. As like our genome, the immune system is further most complicated to understand for modern science.

Article covered and written by- Tushar Chauhan

Article reviewed by- Tushar Kachhadiya

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