Physical Details Identified of Killer T-Cell Activation in T1D

It is well accepted that in T1D self-reactive killer immune cells (killer T-cells) kill beta cells in the pancreas. This killing occurs as a result of a sophisticated means of recognition by the T-cells of entities on the beta cell. A binding complex is thus formed between the T-cell receptor and the beta cell that then results in the activation of the killer T-cell to attack. In this research, sophisticated imaging tools were used to capture this interaction and shed light on how this may promote autoimmunity. These studies showed some surprising results, including a very weak binding interaction between T-cell receptors and beta cell components and a very limited area over which this interaction occurs. According to previous knowledge about the immune system, such a weak interaction should not lead to the activation of these T-cells. These studies highlight the enormous potential for T-cell receptor redundancy to be a causative factor in T1D and raises the question as to why autoimmunity is not more common than it is. These studies clearly show that autoreactive encounters are far more complex and ambiguous than previously assumed.

Reference:

Bulek AM, Cole DK, Skowera A, Dolton G, Gras S, Madura F, Fuller A, Miles JJ, Gostick E, Price DA, Drijfhout JW, Knight RR, Huang GC, Lissin N, Molloy PE, Wooldridge L, Jakobsen BK, Rossjohn J, Peakman M, Rizkallah PJ, Sewell AK. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. (2012) Nat Immunol. Jan 15;13(3):283-9.

Ramifications for Individuals with Type 1 Diabetes:

This is the first study to establish a direct correlation between the physical interaction of T-cells and beta cells and the triggering of the autoreactive process. It also lends support to the theory that autoreactive T-cells may recognize foreign agents first (such as parts of a virus) because of their promiscuous recognition pattern and then go on to misidentify self and mount an autoimmune reaction. Future studies may aid in the design of altered peptides that are slightly different from the self moiety and that can serve to desensitize T-cells rather than activate them, upon recognition.

JDRF Involvement:

This work was partially funded by JDRF.