T-cell tolerance to cytokines may be broken if a native cytokine as a hapten binds to a carrier produced for example by a microorganism. Many viruses are now known to encode homologues of several cytokine receptors. For example, poxviruses such as vaccinia, cowpox and variola encode IFN-alpha/b receptors, as well as TNF-, IL-1-, IL-6- and IFN-gamma receptors. Many are truncated so as to eliminate the transmembrane domains; they are therefore secreted from the infected cells. Some receptors resemble their host counterparts while others have functional similarity but little homology, favouring their role as immunological carriers.

Virus-infected cells release virus-encoded, soluble IFN-alpha receptors (sIFN-alpha-R)
(large viruses, e.g. poxviruses, replicate in the cytoplasm).
The infection also induces the cells to secrete IFN-alpha. B-cells reacting with IFN-alpha epitopes on IFN-alpha-sIFN-alpha-R complexes present virusspecific IFN-alpha-R peptide(s) to T-helper cells (Th), which in turn help B-cells differentiate into IFN-alpha aAb-producing plasma cells.

Broken circle: More effective activation of Th can be expected, if the infected cells are themselves antigen-presenting cells (dendritic cells, macrophages or B-cells).