When the Immune System Attacks

While our immune system functions to protect us from such things as invading microbes, these same defenses can also erroneously turn against the body. One of the major players in both these scenarios is the T-cell, a subtype of immune cell that recognizes and attacks a specific target, also called an antigen.

When an immune response is mounted, the T-cell population proliferates rapidly, creating replicates of the T-cell that recognizes the invader. Proliferation is key in producing enough immune cells to circulate throughout the body and mount the attack. It is also a key step in organ transplant rejection and autoimmune disorders, two situations in which the body attacks itself.

T-cell proliferation can occur in two ways: in response to other cells who present the antigen, or in response to signaling proteins, known as cytokines.

In both organ transplants and autoimmunity, antigen-driven T-cell proliferation is often dampened through immunosuppressants. However, cytokine-driven proliferation can still occur, contributing to transplant rejection, or creating autoimmune T-cells which attack the body.

A recent paper from the Krummel lab works to better understand what differentiates antigen-driven and cytokine-driven T-cell proliferation.

As detailed in an advance online publication in Nature Immunology, the lead author, graduate student Adriana Mujal, began her work in a cellular model, examining a group of proteins important for cell division known as septins.

“Although there’s a body of literature that shows that septins are important for cell division in many different cell types, T-cells appeared to be exempt from this requirement,” said Mujal. However, no one had examined the requirement of septins for distinct types of T-cell division.

Mujal found that cultured T-cells lacking septins still proliferated in response to antigen presentation, in agreement with previous literature. In order to model antigen presentation in vitro, T-cells were cultured with another type of immune cell, bone-marrow derived dendritic cells (BMDC). BMDCs are a type of antigen-presenting immune cell, modeling the interactions that occur in vivo.

In contrast to the response to antigen-presentation, T-cells did not proliferate in response to cytokines involved in T-cell maintenance (IL-2, IL-7 and IL-15).

“This finding in vitro was very surprising,” said Mujal. “It then became a matter of whether this would apply in vivo as well, where you might want to exploit a selective requirement.”

To understand if the same mechanisms were at play in an organism, Mujal moved into a mouse model in which the T-cells lacked septins. The authors examined the lymph nodes and spleen, two sites where T-cell activation and proliferation occurs.

They quantified the number of cells that expressed the surface protein CD8, a marker of a certain group of T-cells, after antigen-presentation or cytokine stimulation. The same differential septin requirement existed in vivo as in cell culture.

This selective requirement allows for a way to target one pathway over the other, which could be important in the clinic.

Based on this work, targeting septins could specifically dampen cytokine-stimulated T-cells, improving organ transplant outcomes and suppressing autoimmunity. Future work will tell whether these therapeutic possibilities can become clinical realities.