CD4 T cell-centric vaccine produces immunopathology and death

CD4 T cells are thought to orchestrate immune response to infections and vaccines. They provide help to CD8 T cells (to become cytotoxic cells and develop memory), B cells (to secrete antibodies) and macrophages (to eliminate intra-cellular microbes in type 1 response).

So, naturally, it is logical to assume that vaccine priming (activation) of CD4 T cells could provide huge benefits to host later. However, human logic and nature logic appears to be at odds in this situation.

The new study published in journal Science showed that CD4 T cell-centric vaccine strategy could backfire with deadly consequences. 

This research led by Prof. Dan Barouch (Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center) analyzed mice immune responses to live virus after vaccination with viral-specific CD4 T cell antigen.  

Surprisingly for the authors and regretfully for the experimental mice, they found that when mice were first vaccinated with intra-cellular microbial vector carrying inserted CD4 T cell specific viral epitope and then exposed to live virus, almost 90% of vaccinated mice died from what appeared to be a cytokine storm.

The authors found that rather than helping to fight virus, vaccine primed CD4 T cells inhibited viral-specific antibody production or maintenance of viral-specific CD8 T cells response.

Mechanistically, the authors found these deadly outcome were mediated by (1) activated viral-epitope specific CD4 T cells; (2) could be prevented by administration of anti-viral antibody or (3) with the simultaneous vaccination with CD8 T cell-specific viral epitope. 

In summary, these results showed that disproportional priming of CD4 T cells during initial vaccination could impair subsequent anti-viral protection. It appears that this outcome maybe specific for viruses producing chronic, long-term infection, since infection of vaccinated mice with viral clone producing acute, short-term infection did not show immunopathology.  

The data in this paper highlight our still so inadequate knowledge of such basic immune response properties as T cell response. If just having simply high frequency of antigen-specific CD4 T cells can produce such immunopathology, how immune system determines beneficial frequency of CD4 T helper (CD4 T_H) cells? It's just another of nature's mystery to be solved.     

David Usharauli