Tolerance versus Activation based on the duration of T cell-APC contact

It seems we know a lot about T cell activation and central tolerance but somehow little when it comes to rules and mechanisms of peripheral tolerance, although in my opinion the latter is essential to understand and manage autoimmunity/ development of malignancy and even chronic infections.

A group from the University of California at San Francisco in collaboration with scientists from Stanford (1) did fabulous work to look into what drives CD4+ T cell tolerance versus activation to a systemic self antigen(sOVA) in two transgenic mice models (one that is lymphocyte deficient [sOVA-Tg/Rag-/-] and one that is lymphocyte sufficient sOVA-Tg). They examined both cytokine and activation/proliferation markers. They also used two-photon laser scanning microscopy to examine polyclonal and antigen-specific T cells in an inguinal lymph node from the mice and acquired 4D images (using a special software).

They found a prolonged activation of NF-κB in the lymphopenic host (in whom autoimmunity would develop) but a shorter-lasting activation in the immunocompetent host (by 8-hour posttransfer). Looking into the T cell-APC interaction, they found a significant decrease in the movement velocity of Ag-specific T cells in both hosts at 4 hours posttransfer, indicating that even in conditions of tolerance (in the lymphocyte-sufficient host) Ag recognition is needed but that rather a stop-signal is delivered. The striking difference was the duration of interaction with the APC: continuing for 18-hours in the host to develop autoimmunity while in the Ag-tolerant host, the Ag-specific T cells had regained their motility and moved away by this time. Therefore, indicating that the duration of this interaction is important in determining the fate of TCR signaling.

My comments :

· Do you notice the association between lymphopenia and autoimmunity? I must say, I used to think of it otherwise (mistaken) but I had the chance to see a patient with T cell deficiency and multiple endocrinopathies (diabetes and thyroid disease). Notice that this is not primarily due to depletion of T regs [actually in this paper they have treated the lymphopenic mice with anti-CD25 and found the same results. The authors propose reduced competence for DC and cytokines in cases of lymphopenia as a possible mechanism].

· Imaging in Immunology is a nice point here: They used Two-Photon laser scanning microscopy (TPLSM) to visualize and quantify the movement and interaction between APC-T cell. I had a discussion with the responsible person in the core microscopy about it (Radu Moldoven) and this modality is available and can be used to visualize anything bigger than 350nm but the tracking software is still unavailable at our university.

· Q: what happens next after Tcell-APC interaction in conditions of tolerance?

I hope you find this post useful

Thanks

(1) Katzmana SD, O’Gormanb WE, Villarinoa AV, Galloa E, Friedmana RS, Krummela MF, Nolan GP and Abbas AK. Duration of antigen receptor signaling determines T-cell tolerance or activation. PNAS. 2010; 107 (42): 18085-18090.