Immune cells are the "health guards" that protect the human body and can eliminate pathogens, aging and necrotic cells and even mutated cancer cells. As the main combatant of the immune cell family, T cells are sometimes "exhausted". How to effectively alleviate cell failure, resurrect T cells with full blood, and continue to work for the human body has become an important direction for scientists to explore.

Recently, a research report published in "PNAS" (Proceedings of the National Academy of Sciences) found a solution!

The report pointed out: The state of T cell exhaustion can be reversed by returning fresh immune cells, and even chronic viral infections can be treated! It has created a new world for immune cells to treat infectious diseases and cancer.

 
△ During chronic viral infection,
Antigen-specific CD4 T cells help save exhausted CD8 T cells

01
Why do T cells fail?

As the main force of immune cells, T cells will be activated when the human body is infected. A large number of T cells will gather to fight the infectious pathogen until the pathogen is completely eliminated.

When the human body is in an acute infection, once the antigen is cleared or the inflammation subsides, the effector T cells will differentiate into memory T cells to continue patrolling in the body, and produce a strong memory response after the secondary infection, maintaining continuous and effective combat effectiveness. No antigen stimulation is required to maintain.

However, when the human body is chronically infected, antigens and inflammation continue to exist, and T cells are continuously stimulated and are in a state of being activated. For a long time, T cells lose their effector functions in a certain regularity and eventually become exhausted. If the infection is severe or lasts too long, T cells may even be lost.

02
Cell reinfusion can effectively relieve exhaustion

In T cells, there are two types of cells, CD4 T cells are helper cells, and CD8 T cells are the main killer cells.

Researchers analyzed experiments in mice infected with chronic lymphocytic choriomeningitis virus (LCMV) and found that long-term virus infection can cause the failure of CD4 T cells, and the failure of CD4 T cells directly leads to CD8 T cells The massive exhaustion.
 
△ CD4 T cells shrink slowly in chronically infected mice

This is also the main reason for reducing the ability of T cells to kill enemies. These two types of cells have complementary effects, and CD4 T cells play a key role in regulating the response of CD8 T cells to chronic viral infections.

When the researchers reinfused the CD4 T cells that were not chronically infected by LCMV into mice chronically infected by LCMV, a miracle happened!
 
The originally exhausted CD8 T has regained its vitality! The CD8 T cells in the chronically infected mice of LCMV restore proliferation and cytokine production, reduce the burden of the virus and exert their effects.

 
△ CD4 T cell reinfusion
Helps enhance LCMV-specific CD8 T cell response

As a control group, the researchers also returned uninfected CD4 T cells to other uninfected mice, and there was no mass proliferation of CD8 T cells.

These results indicate that re-infusion of immune cells can improve the immune cells consumed by chronic inflammation and allow the body to restore the function of fighting pathogens.

03
Combined with PD-1, the effect is more significant

Although reinfused CD4 T cells can enhance the function of depleted CD8 T cells, these CD4 T cells express high levels of programmed cell death (PD)-1 inhibitory receptors. In order to further enhance the efficacy of CD4 T cells, researchers began to try a new method.

Through reinfusion of CD4 T cells and combined PD-1 treatment, an incredible conclusion was reached: the virus titer of chronically infected mice was 10 times lower than that of mice that did not receive the combined treatment! Even in some mice, the presence of the virus is basically undetectable!

△ PD-1 blockade improves the function of LCMV-specific CD4 T cells

By blocking the PD-1 pathway, the researchers increased the ability of the infused LCMV CD4 T cells to produce effector cytokines, improved the rescue of exhausted CD8 T cells, and resulted in a significant reduction of the virus.

These results indicate that CD4 T cell immunotherapy alone or in combination with blocking inhibitory receptors may be a promising method for the treatment of CD8 T cell dysfunction in chronic infections and cancer.
 

△ PD-1 blockade supplements CD4 T cell therapy,
Enhance the function of exhausted CD8 T cells and further reduce the viral load

Therefore, short-term blockade of inhibitory signals such as the PD-1/PD-L1 pathway supplements the transfer of CD4 T cells, improves the response of CD8 T cells, and significantly enhances virus control during chronic LCMV infection.

In this very strict chronic LCMV infection model lacking the help of CD4 T cells, this significant virus reduction has never been seen before. These results will further support the use of combination therapy to solve chronic infections and even cancer.