Friday, September 20, 2013

Do T Cells Have A Need for Speed?

A recent study focuses on the time required for T cells to identify, interact with, and mount a response against pathogens within the human body.

The life of an infectious pathogen is not an easy one. Should a virus, bacterium, prion, or fungus manage to make it past the body’s first line of defense – obstacles including anatomical barriers such as the skin and physiological barriers like the hostile low pH environment of the stomach – it still must face a barrage of innate and adaptive immune responses before successfully establishing itself.  Once a pathogen has entered the body, the innate immune system – defined as the cells and mechanisms that defend the host against foreign organisms in a non-specific manner - may recognize the non-self intruder and induce an immune response. This eventually leads to the activation of the adaptive immune system and, in turn, of white blood cells like T and B lymphocytes (or T and B cells) which quickly identify and eliminate the pathogen. It is the accuracy and speed of these cells’ responses that makes the adaptive immune system so effective in protecting the body against infection. So the short answer is, yes, T cells do have a need for speed. To contest to this, a recent study now suggests that that once a T cell senses an antigen – a task that can take only a matter of seconds – it can decide the fate of the invading microorganism within minutes.

This new study, released in The Journal of Immunology just a few months ago, tested T cells under various conditions to judge their aptitude for identifying invading pathogens. According to the authors, there are four factors that limit the ability of T cell to recognize pathogens. These include: 
  1. T lymphocyte bears a single T cell receptor (TCR).  This means that any given T cell can only recognize a single antigen structure. Therefore T cells are very sensitive to interactions but are vastly outnumbered by antigen presenting cells (APCs)!
  2.  Thousands of proteins can be used to generate the peptide - major histocompatibility complex (pMHC) on the invading cell surface. The T cell must be able to quickly recognize one to a few of these intricate complexes on the cell to identify it.  
  3. Exposed cell pMHCs may differ by a few amino acids. Despite this, the TCR must still recognize them and be able to properly bind to trigger a T cell response.    
  4. The TCR and pMHC complex is only ~ 14 nanometers in length. One nanometeris one-billionth of a meter, so these are miniscule complexes that must somehow closely interact in a stable way. This interaction is strongly dependent on the tiny movements made by the T cell membrane.

These limiting factors require that we know two important things about T cells if we want to understand the speed and specificity of the antigen detection process. Firstly, we need to know the how often a T cell and an antigen presenting cell contact each other and for how long. Secondly, we need to know if and how T cell membrane motions are altered as a result of antigen detection.
To determine these features of the T cell detection process, the authors used a technique called internal reflection fluorescence microscopy or TIRFM. TIRFM is used to image the contact area between the T cells and an antibody coated surface. While many of the authors previous experiments used interference reflective microscopy (IRM) to study T cell-antibody interactions, they found that using TIRFM allowed for better cell imaging and, therefore, a more reliable method to view and time T cell interactions.  These TIRFM experiments showed that the T cells were binding with and spreading across the antibody coated surfaces within one minute of contact.  In addition, T cells were seen to associate with the antibodies for less than 30 seconds before making their decision to trigger more coordinated cell responses that result in the further spread of T cells in search for antibodies and the production of proteins that would aid in an immune response.  The authors also suggest that the tiny membrane movements of the T cells are a way for the cell to rapidly test its environment for antigens.  

So what is so important about these experiments? For one, they provide evidence of just how fast a T cell can identify and respond to an antigen, thus giving us a better understanding of how quickly and efficiently our immune system really works. Additionally, it provides the basis for future experiments in which one could test how long after T cell-antigen interaction other T cell triggered immune proteins and cell-cell signaling would arise.  It lays the base for us to learn even more about the intricacies of our own body.

For general information on the immune system, see: http://missinglink.ucsf.edu/lm/immunology_module/prologue/prologuehome.html

For information on T-lymphocytes, see:

To see more recent articles from the Journal of Immunology, see: http://www.jimmunol.org/content/current


Primary Source:

Brodovich A, P Bongrand and A Pierres. T lymhpcytes sense antigens within seconds and make a decision 
within one minute. 29 July 2013. J Immunol. 191:2064-2071.

Secondary Sources:

Medshitov R and CA Janeway Jr. Decoding patterns of self and nonself by the innate immune system. Science 12 April 2002 296:298-300 http://stke.sciencemag.org/cgi/reprint/sci;296/5566/298.pdf

Axelrod, Daniel. (2001)Total Internal Reflection Fluorescence Microscopy in Cell Biology. Blackwell Publishing Ltd 2:764- 774. http://dx.doi.org/10.1034/j.1600-0854.2001.21104.x


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