Cross-Tolerance

Here is the second question: Is there spreading of tolerance just like epitope spreading in immune responsiveness?

I have been wondering about this for very long because of an unusual observation in my research.

The term “Cross-Tolerance” I will refer to here is the one suggested by two investigators working in transplant immunology from Harvard and Beth Israel Deaconess medical center (1) and specifically means that “T cell tolerance to one set of antigens would result in the development of tolerance to other unrelated antigens due to cross-reactivity” (1). In the literature there is some reference to cross-tolerance in the context that DC can either do cross-presentation to cross-prime T cells (I posted before) or cross-tolerize T cells (which is when self antigens are cross-presented in which case those T cells that recognize such antigens will be deleted, this is different from what I am referring to here where cells becoming tolerant to one antigen (be itself or not) develop an unexpected tolerance to another unrelated antigen).

Note that in epitope/ antigen spreading of immune response this is based on that the disease process/ tissue damage will result in exposure of new epitopes/ antigens to which another immune response will develop. So, cross immune tolerance is not the reverse of epitope spreading because it is , as suggested by the investigators in this recent article about cross-tolerance(1), an issue of cross-reactivity of the TCR (they refer to “TCR plasticity”). I would also quote this: “structural criteria rather than primary sequences may dictate the TCR recognition of different antigenic epitopes, which makes it exceedingly difficult to predict the crossreactive nature of TCRs” (1). This is something we did discuss in class in the context of development of immune response to graft antigens because of the cross-reactivity of the TCR and JJ Cohen had his nice live models of the two apples and the dishes to clarify that. Here, this is extended to the development of tolerance not just responsiveness. I think that because it is a cross-reactivity issue, I would not expect it to have a specific marching sequence of spread the way epitope spreading is.

However, it is of note that the paper presents a “suggested mechanism and definition” not results of a specific study.

So what, why should this matter?

1. Ofcourse for me it does because I had a kind of a persistent finding of what I assume is some form of tolerance to a one specific control antigen and disappearance of this once immune responsiveness is being restored. A weared observation that had no explanation so far.

2. There is a long discussion in the paper about the implications of this in transplant immunology: for example, would inducing tolerance of T cells to specific antigens related to the graft result in loss of important protective responses to some pathogens?, so would it be best to choose a graft with minimal cross-reactivity with those of the recipient not only to reduce the chance of rejection but the possible harms of cross-tolerance upon tolerance induction and therefore, the chance of viral and other infections to follow. I think this is a fine line though still going in the same direction.

Does anyone have any experience with this? Any comments/ suggestions?

I am sorry if this post comes late in the course, I just found this last week.

(1)Zhao Y and Li X. Cross-Immune Tolerance: conception and its’ potential significance on transplantation tolerance. Cellular and Molecular Immunology. 2010; 7: 20-25.