Why is graft-vs-host so selective against phylogenetically close cells?
Since this has gone unanswered, I'll give my best guess. My guess is that closely related MHC* can still be recognized by CD4/CD8 (while not in distant relatives phylogenetically), but, the MHC + eventual bound peptide will not be recognized as self (with or without bound peptide), since its structure may differ even when binding self-antigen peptides that were exposed to T-cells during central tolerance &quot;traning&quot;.
I am very intersted in what the established explanation is including references, and invite better answers if there is competence to produce that.
*in the context of the question, i.e., at species level, within species sufficiently close MHC genes are not attacked at all and compatible.
I'll attach potential reference to my guess that ability to recognize MHC as... MHC, decreases with phylogenetic distance,
Vignali, D. A., Moreno, J., Schiller, D., &amp; Hämmerling, G. J. (1992). Species-specific binding of CD4 to the beta 2 domain of major histocompatibility complex class II molecules. Journal of Experimental Medicine, 175(4), 925–932. https://doi.org/10.1084/jem.175.4.925
that references this,
Lamarre, D., Ashkenazi, A., Fleury, S., Smith, D., Sekaly, R., &amp; Capon, D. (1989). The MHC-binding and gp120-binding functions of CD4 are separable. Science, 245(4919), 743–746. https://doi.org/10.1126/science.2549633
that says this,

&quot;although human and mouse CD4 share a high degree of amino acid sequence identity (19), the murine homolog does not bind gpl20 (11) and does not interact with the human class II MHC molecule HLA-DP as assessed by functional and adhesion assays (20). &quot;