T Cell Receptors: Shaping up to Fight Infection

The human immune system has many different types of cells which form a well-organized and well -armed force that has the ability to combat almost any bacteria or virus which is trying to gain access to our bodies. Among its ranks, the immune system has an elite fighting force composed of T cells, members of a group of white blood cells known as lymphocytes, which plays a vital role in cell-mediated immunity. Cell-mediated simply means that unlike B cells which can secrete antibodies to target bacteria and viruses at a distance, T cells need to get up close and personal when dealing with pathogens. More specifically, T cells are involved primarily in combating viruses by using various mechanisms including target host cell killing and phagocytosis of free floating virus particles.

The chief mechanism used by T cells to combat various infections involves utilizing their unique T cell receptors (TCRs). These receptors allow T cells to identify specific foreign entities and eliminate them from the body. In order to accomplish this task, T cells must first be presented with a piece of the pathogen known as an antigen which can bind to the TCR. Depending on the tightness of the fit, or the affinity of the interaction, the TCR will either trigger the T cell to become activated or it will remain senescent. Due to the specificity of this interaction, the T cells which are generated are geared to combat specific pathogens. This in turn lays the foundation for an adaptive immune response.

Adaptive immunity is the part of our immune system which kicks in after an infection has bypassed our innate defenses such as our skin, the mucous in our nose, or the many white blood cells which combat pathogens nonspecifically. This type of immunity is adaptive because it produces a highly specialized response against a particular pathogen after the pathogen has already entered our bodies. In order for T cells to participate in an adaptive immune response they first must make the transition from a naïve T cell, which is one that has not interacted with a specific antigen, to a mature T cell, one that has contacted an antigen. The transition of a T cell from naivety to maturity is an area studied by Rashmi Kumar and her colleagues, and their findings were recently reported in the journal Immunity. Specifically, they examined the difference between T cell receptors (TCRs) on naïve and mature T cells in the hope of discovering the reason why memory T cells respond more rapidly and robustly when confronted with an antigen than do naïve T cells. A rapid T cell response is important for adaptive immunity because it allows for memory T cells, those that continue to circulate in our blood after an infection, to jump into action should the same pathogen try to infect a person twice.

The researchers began their quest by looking at the different sizes of TCRs on both naïve and mature T cells. In doing so they labeled the TCRs on both stimulated and non-stimulated lymphocytes with gold particles. Next, the TCRs were viewed using electron microscopy where it was discovered that the stimulated lymphoblasts actually had more and larger TCR conglomerations, called oligomers, on their plasma membrane surfaces than did the un-stimulated lymphocytes. To test whether the same relationship held true in live mice, the researchers isolated naïve and memory CD4⁺T cells from mouse spleens and lymph nodes. CD4⁺T cells are also known as helper T (Th) cells due to their role in assisting B cells with antigen recognition and the production of an adaptive response. CD4 is a surface protein which these cells express to assist in the binding of Th cells to activated B cells. Another type of T cell, CD8⁺T cells or killer T cells, is the T cell which actually directly combats foreign pathogens through means such as targeted host cell killing. Both of these types of cells have been shown to react preferentially with oligomeric class II MHC-peptide (pMHC) complexes, revealing that both the TCR and MHC molecules need to form oligomers if a successful interaction is to occur between B cells and T cells (1). The CD4 cells were then subjected to the same gold binding and electron microscopy procedure, and once again it was revealed that larger TCR oligomeric complexes formed in vivo when cells encountered their specific antigen. The next hypothesis to be tested was whether or not these larger and more numerous TCRs actually led to higher antigen sensitivity, which would explain why stimulated and memory T cells possessed them. T cells were once again generated to be either naïve or antigen-experienced and were stimulated with OVAp, a piece of a protein derived from eggs. Upon being stimulated it was observed that antigen-experienced T cells were 100 to 3,000 times more sensitive than the naïve T cells. This was determined to be caused by an increase in CD69 and IFN-y, which are produced by activated T cells during an adaptive immune response. The next logical question becomes: how do these TCRs increase the sensitivity of T cells? T cells are activated when their TCRs bind to foreign antigens on major histocompatibilty complexes (MHCs). The MHC molecules on the surface of antigen presenting cells (APCs) form clusters which present the foreign antigen. The quality and quantity of binding between TCRs and MHCs has been shown to influence many aspects of T cell activity, such as T cell differentiation and long term survival of memory T cell populations (2). Interestingly, the avidity, or the number of binding interactions, for MCH formation is increased in the presence of TCR oligomers. Thus because of the formation of these TCR oligomers on mature and memory T cells, these cells can react better to an antigen than can immature T cells.

This research provides a key stepping stone to understanding and possibly someday harnessing the power of a T cell to fight infections. It is fascinating to even imagine being able to increase the effectiveness of our own body’s immune cells by perhaps simply taking a drug which promotes TCR oligomer formation. However, for this to become a reality further research must be conducted to better understand the mechanisms by which TCR oligomers are formed and how these formations interact with MHC molecules.

Reference: Kumar, R., Ferez, M., Swamy, M., Arechaga, I., Rejas, M.T., Valpuesta, J.M., Schamel, W.W.A., Alarcon, B., van Satan, H.M. 2011. Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes. Immunity.

Other citations:

(1) Stones, J., Lawrence S.J. 2006. CD8 T cells, like CD4 T cells, are triggered by multivalent engagement of TCRs by MHC-peptide ligands but not by monovalent engagement. Journal of Immunology. 176: 1498-1505.

(2) Chulwoo, K., Williams, M.A. 2010. Nature and nurture: T-cell receptor-dependent and T-cell receptor-independent differentiation cues in the selection of the memory T-cell pool. Immunology, 131:310-317.