Immune Cell Survival:
Walking a Tightrope

Anthony T. Vella, Ph.D.
Assistant Professor of Microbiology
OSU/LPI Affiliate Investigator

The immune system is made up of two components. The most primitive arm of the immune system is referred to as "innate" immunity. Innate immunity mainly involves the action of cells like macrophages, as well as serum proteins, which control infection in a nonspecific fashion. For example, macrophages efficiently engulf bacteria, protozoans, viruses, and particulate substances that they encounter in the body.

Upon engulfment, macrophages will try to destroy the pathogen (Fig. 1a). The other component of the immune system, the "adaptive" immune system, contains B and T cells that respond to challenge by foreign particles in a much more specific manner. Both B and T cells originate in the bone marrow and then migrate to other organs and tissues. The surfaces of B cells are coated with antibody molecules that are capable of binding antigens (protein molecules that can induce a response by the immune system) in a very specific fashion. Once stimulated, the B cells will release the antibody molecules into blood, which allows them to counteract the antigens (Fig. 1b). T cells are divided into two subpopulations, CD8 and CD4 cells. CD8 T cells are known as killer cells.

Figure 1
For example, if a skin cell presents a viral protein as a result of its infection by a virus, the CD8 T cell will recognize this cell as abnormal and proceed to destroy it (Fig. 1c). CD4 T cells, or helper cells, are regarded as the "quarterback" of the immune system. They are intimately involved in regulating antibody production and activate CD8 T cells so that they can become better killers. CD4 T cells are also critical in enhancing or subduing inflammation, which they do by secreting proteins called cytokines that control cell function (Fig. 1d). CD4 T cells are instrumental in facilitating many autoimmune diseases like arthritis and multiple sclerosis, in which the immune system responds abnormally to the body's own molecules (called "self antigens"). It is now clear that CD4 T cells are also a main target for the human immunodeficiency virus (HIV) that causes AIDS. Understanding how to control CD4 T cells will allow us to develop better vaccines, abolish many forms of autoimmunity, and control allergies.

Tolerance and Autoimmunity

In healthy individuals, the immune system is not stimulated by self antigens, but is capable of attacking foreign pathogens. Understanding this balance between tolerance to self antigen and activation towards a foreign pathogen is a critical step in being able to treat auto-immune disease and allergies. In early development, the body learns not to respond to self antigens, resulting in "tolerance." In the last half of this century, it has become clear that exposure to soluble antigens leads to the induction of tolerance, which means that the host will not produce a strong antibody response nor will T cells become activated in response to being challenged again with the antigen. The question that has long perplexed immunologists is: "Why don't we respond to self antigens and how is this tolerance circumvented during autoimmunity?"

Autoimmune diseases are nearly always associated with inflammatory responses. Similarly, pathogenic infections produce inflammation. Both types of responses result in the long term survival of certain T cells that specifically respond to particular antigens. For example, in the aftermath of a viral infection, antigen-specific T cells accumulate. In autoimmune responses, autoreactive T cells accumulate in large numbers and are more responsive to autoantigens on subsequent recognition. Thus, these "memory" T cells are not tolerized, but instead persist for long periods of time. We hypothesize that both autoimmune and antigenic responses, either to self or foreign antigens, develop in similar ways. A common denominator for these T cell responses is inflammation. A cascade of events follows the recognition of antigens by T cells: the T cells increase in size, begin to express new surface molecules, secrete factors that promote growth and differentiation (cell maturation), proliferate robustly, and then many of these cells will die.

Figure 2

Our experimental results show that when an inflammatory response accompanies this progression, many of the T cells will survive, rather than die (Fig. 2). Several years ago we began to investigate how inflammation permits T cells to avoid death. Inflammation is a common process that produces swelling and redness (erythema) that we all have experienced at one time or another when we are bruised or cut. It is the body's response to prevent infection and repair the damaged site. Macrophages are very active in this process; by reacting quickly and efficiently, they produce pro-inflammatory cytokines, which are proteins that regulate cell adhesion, growth, differentiation, homing, and trafficking. Of the pro-inflammatory cytokines, tumor necrosis factor alpha (TNFa), interleukin-1 beta (IL-1b), and interleukin-6 (IL-6) are the most widely studied. These particular cytokines are most interesting because they are made in great abundance during inflammatory reactions.

We wished to determine experimentally whether TNFa is involved in rescuing T cells from antigen-driven death. These experiments showed that in mice undergoing an antigenic challenge accompanied by inflammation, T cells were not rescued from death when TNFa was neutralized. This observation led to the conclusion that TNFa is pivotal in keeping T cells alive. Later, we determined that IL-1b is also critical for T cell survival. Two important points can be derived from these experiments: 1) certain factors and conditions influence T cell survival, and 2) the innate and adaptive immune systems are integrally connected with each other and are in constant cooperative communication.

Recent Work on Pro-Inflammatory Cytokines

With support from the Linus Pauling Institute, we recently began a detailed investigation of the role of IL-6 in T cell survival. Knowing that IL-6 could keep unstimulated T cells alive, we postulated that IL-6 may be involved in preventing activated T cells from dying. Our experiments confirmed that antigen-activated T cells were less likely to survive during an inflammatory reaction in the absence of IL-6. Further experiments demonstrated that neither TNFa nor IL-1b could rescue T cells from death in IL-6 deficient mice. This led to the conclusion that TNFa and IL-1b actually induce IL-6. Interestingly, IL-6 has been implicated in autoimmunity and allergies. For instance, IL-6 has been detected in inflamed arthritic joints, and it is possible that the IL-6 found in these joints permits undesirable T cells to survive.

Other cytokines, such as IL-4, which is intimately involved in allergic responses, are also involved in the life and death of T cells. Like IL-6, IL-4 can prevent T cell death. It may be possible to control allergies by selectively destroying the T cells that promote allergic responses. In this regard, however, T cells are clever. The allergy-inducing T cells are the same ones that make IL-4, so they keep themselves alive by producing large quantities of IL-4. We are currently exploring this process in our laboratory by analyzing the way in which IL-4 binds to T cells.

This emerging knowledge is critical for the development of strategies to control debilitating afflictions like autoimmunity and allergies. When we more fully understand exactly how cytokines like IL-4 and IL-6 control T cell survival, we will be able to create protocols to destroy the undesirable T cells. However, our success will be akin to walking a tightrope because T cells are very important when fighting infection or cancer. In these circumstances, we want to keep as many T cells alive as possible. Recently, we have found that vitamin C can block the death of antigen-activated T cells in culture. Of course, this is a beneficial effect when we are challenged by pathogens or abnormal cells. We plan to test this very favorable effect in mice fed vitamin C and infected with a pathogen.

The exquisite balance of factors that control T cell death and survival is the continuing focus of our research. Further understanding of the specific roles of IL-4, IL-6, and vitamin C in maintaining proper balance will be extremely useful in therapeutically correcting autoimmune diseases and allergies.

Last updated May, 1998

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