T Cell Receptors: Shaping up to Fight Infection

The human immune system has many different types of cells which form a well-organized and well -armed force that has the ability to combat almost any bacteria or virus which is trying to gain access to our bodies. Among its ranks, the immune system has an elite fighting force composed of T cells, members of a group of white blood cells known as lymphocytes, which plays a vital role in cell-mediated immunity. Cell-mediated simply means that unlike B cells which can secrete antibodies to target bacteria and viruses at a distance, T cells need to get up close and personal when dealing with pathogens. More specifically, T cells are involved primarily in combating viruses by using various mechanisms including target host cell killing and phagocytosis of free floating virus particles.

The chief mechanism used by T cells to combat various infections involves utilizing their unique T cell receptors (TCRs). These receptors allow T cells to identify specific foreign entities and eliminate them from the body. In order to accomplish this task, T cells must first be presented with a piece of the pathogen known as an antigen which can bind to the TCR. Depending on the tightness of the fit, or the affinity of the interaction, the TCR will either trigger the T cell to become activated or it will remain senescent. Due to the specificity of this interaction, the T cells which are generated are geared to combat specific pathogens. This in turn lays the foundation for an adaptive immune response.

Adaptive immunity is the part of our immune system which kicks in after an infection has bypassed our innate defenses such as our skin, the mucous in our nose, or the many white blood cells which combat pathogens nonspecifically. This type of immunity is adaptive because it produces a highly specialized response against a particular pathogen after the pathogen has already entered our bodies. In order for T cells to participate in an adaptive immune response they first must make the transition from a naïve T cell, which is one that has not interacted with a specific antigen, to a mature T cell, one that has contacted an antigen. The transition of a T cell from naivety to maturity is an area studied by Rashmi Kumar and her colleagues, and their findings were recently reported in the journal Immunity. Specifically, they examined the difference between T cell receptors (TCRs) on naïve and mature T cells in the hope of discovering the reason why memory T cells respond more rapidly and robustly when confronted with an antigen than do naïve T cells. A rapid T cell response is important for adaptive immunity because it allows for memory T cells, those that continue to circulate in our blood after an infection, to jump into action should the same pathogen try to infect a person twice.

Tissue Associated Tregs May Explain Why Some Children Have Persistent Ear Infections

Maybe you know a small child who just can’t seem to shake an ear infection. Maybe, at one time, you were that child. There is good news; immunologists may be one step closer to understanding why the infection is sticking around.

Streptococcus pneumoniae (pneumococcus) is a harmful bacterium that causes millions of deaths every year. Pneumonia, meningitis, and ear infections (otitis media) are all the handiwork of this bacterium. Young children often carry pneumococcus until age three. By that time, their adaptive immune response (not the primary line of defense but the very specific, memory based line of defense) either prevents the infection or quickly removes it with the help of the immune cells in the NALT (nasal-associated lymphoid tissue).

It is curious, then, how some children who display immunological memory for the pathogen continue to carry the infection in their nasopharynx. A recent study Zhang et. al. in PLoS Pathogens suggests that regulatory T cells (Tregs) may be responsible for allowing the infection to persist.

Toll-like Receptor 7 is the Retrovirus Sensing Receptor in Mice

Retroviruses tend to be of great interest to the general public, because of all the media attention given to widely problematic ones, such as the Human Immunodeficiency Virus (HIV). Before effective vaccines against retroviruses like HIV can be produced, a basic understanding of how the immune system responds to them is imperative. When a retrovirus enters the human body, many are known to overcome the immune system, and possibly inhabit the host long-term. However, some animals have developed very efficient immune responses, which allow them to essentially evade or kill the virus. Scientists can study animals with this ability, like mice, to better understand the specificities of their immune systems that facilitate its advantage over the retrovirus, in hopes of relating their findings back to humans.

The first line of defense in the immune response is the innate immune system. The innate immune system is often thought of as “natural,” and provides non-specific protection against foreign invaders (1). Innate defenses are found all over the body, and include physical barriers like skin and mucus. Additionally, the innate immune system responds to pathogens in a generic way and has multiple mechanisms for killing and removing invaders. Most times, the innate defenses are successful. However, if the innate immune system is unsuccessful, it is responsible for triggering the secondary reaction of the adaptive immune system. The adaptive immune response is a specific response to a particular pathogen (foreign invader) and is usually only triggered by those entities that successfully overcome the innate immune response (1). Previous research has shown that in some strains of mice, the innate immune system senses the virus and triggers the appropriate adaptive immune response specific to the virus (2). So although the adaptive immune response is responsible for controlling retroviruses in mice, the first, critical innate virus-sensing step is still not confirmed.

Viruses are unique because they are recognized by endocytic pattern recognition receptors (PRR) on host leukocytes (white blood cells) that detect replication intermediates (nucleic acids) produced by the virus (2). However, it is unknown whether these viral sensors play a vital role in virus sensing in vivo, which is why animal models are very helpful. A recent paper by Kane et al. (2011) is therefore broadly asking whether retroviral replication intermediates are recognized by the innate immune system and further, if they are critical components for the adaptive immune response.

Men: Beware the ETS Family of Transcription Factors-It May Control Immunity Genes Involved in Prostate Cancer

Cancer is a state of abnormal and uncontrolled cell growth that can potentially spread throughout the body. Cancerous cells have adverse effects, which the body has many defenses against in order to prevent tumor growth and cancer development. The immune system is thought to aid in the suppression or promotion of tumor growth by exerting multiple cellular controls over the death or proliferation of certain cells (Lin and Karin, 2007). With vast numbers of people being affected by cancer on a daily basis, it is important to identify cellular differences between cancerous and healthy states. Identifying changes that might be associated with the onset of cancer proliferation can potentially lead to better understanding of the onsets of cancer.

The prostate, a gland found in males that stores liquid that carries sperm, is highly susceptible to inflammation and cancer (Eisenburg Center, 2005). Prostate cancer is becoming increasingly common in adult males: In fact, in 1990 prostate cancer became the most frequently diagnosed cancer in men, constituting 29% of all cancers found in men (American Cancer Society, 2011). With such alarming numbers of incidence, prostate cancer has become a great health concern of epidemic proportions. However, the theory behind the recent drastic increases may not be solely attributable to an increase in the prevalence of the disease, but instead to new tests, such as the PSA (prostate-specific antigen) test. The PSA test allows for more accurate and determinate prostate cancer detection (Levy, 1995). Even though the higher number of reported cases appears daunting, the PSA test has had the positive effect of detecting the cancer earlier for effective treatment, resulting in decreasing mortality rates. Therefore, PSA tests may allow for prostate cancer to be detected at younger ages, resulting in more healthy, robust men being diagnosed with greater chances of survival with treatment (Hsing, Tsao, and Devesa, 2000).

Something to squeak about: “Dirty” Wild Mice may be Better Models for Immunological Studies

When we become infected with a virus or develop cancerous cells, our bodily friend group expands as natural killer cells (NK) come to our defense to protect us from these nasty invaders. Like a trained body guard, the NK cells immediately respond to enhance our immune system by defending us against microbes and tumors in our bodies. They have granules in their cytoplasm which host proteins such as perforin and proteases (granzymes) which are released near a pathogen. Upon release, the perforin perforates holes in the cell membrane of the pathogen through which the granzymes and associated molecules can enter to induce apoptosis[o1] .  Interferons and macrophage-derived cytokines activate NK cells to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells.

Much of what we have learned about immunological processes such as these have stemmed from research on animal models. Mice serve as an important model organism to study molecular mechanisms in immunology.  NK cells from laboratory mice respond poorly to stimuli unless the mice are treated with toll-like receptor (TLR) agonists, cytokines or infection. Previous studies indicate that NK cells are extremely low in lymph nodes (LNs), to lack perforin or granzyme B (Gzmb) and to die prematurely in cytokine absent cultures (Fehniger et al. 2007; Long 2007). This starkly contrasts with NK presence in humans which are profuse in LNs, contain perforin and Gzmb and survive better. Previously these discrepancies were attributed to the fact that the differing species had varying NK cells.  NK cells were believed to be short-lived and innate.  Recent studies, however, suggest that NK cells may be live longer than was previously thought.

Breaching the Great Wall: Attack of the Immune Cells on the Central Nervous System

The brain is considered the most complex living structure known in the universe. This organ is responsible for controlling all bodily functions ranging from heart rate to motor functions. Given the complexity and importance of the brain, it is vital that proper defenses are maintained, one of which is the blood brain barrier. The blood brain barrier (BBB), as the name implies, serves as an anatomical barrier against invading pathogens by blocking their entry into the brain. Think of it as the Great Wall of China that was built in order to protect the Chinese empire against invasion by nomadic tribes. In this analogy, the brain would be considered the Chinese empire. Similar to the bricks and stones making up the Great Wall, tight junctions present between the endothelial cells of the blood vessels make up the BBB and they function to allow passage of only certain molecules such as oxygen. Even molecules such as glucose must undergo an active transport mechanism in order to pass through the BBB. The central nervous system (CNS) is considered an immunoprivileged organ in that CNS antigens are not accessible to immune cells in the periphery. Likewise, peripheral immune cells and pathogens cannot easily penetrate the BBB.

During the course of various neurological diseases such as multiple sclerosis (MS), vascular dementia, and stroke, this great wall becomes compromised thereby triggering the infiltration of immune cells into the CNS. This process in turn causes inflammation. Studies on animal models of these diseases aim to unravel the mechanisms by which certain immune cells breach the BBB (Simka, 2009). Unraveling such mechanisms provides therapeutic targets for future investigations in the hope of finding an effective treatment.

Not a Crazy Idea: TLRs Implicated in Psychiatric Disorders

Innate immunity lays the foundation of the immune response and provides the first line of defense against invading pathogens. Toll-like Receptors (TLRs) are an essential aspect of this response, think of them as security guards on the outside of a cell. TLRs belong to a class of receptors which recognize unique, yet general, patterns on bacteria, viruses, or even fungi, making them members of the pathogen-recognition receptor (PRR) group. TLRs generally reside on leukocytes, mostly monocytes, dendritic cells (DCs), and neutrophils. When a pathogen binds to the receptor an intracellular signaling cascade is initiated which leads to the activation of Nf-kB, a pro-inflammatory transcription factor. Simply put, NF-kB leads to the production of cytokines, immune messengers, which can affect other immune cells and promote inflammation. The inflammatory response is characterized by localized swelling caused by vasodilation, an increase in diameter of the blood vessels. This response allows more leukocytes to travel to the area of invasion to remove the pathogen.

When asked to imagine the immune response the first thing which comes to the mind of most is the illness, usually a cold, virus, or something more severe, such as HIV. However, recent research has linked TLR deregulation to two psychiatric illnesses, schizophrenia and bipolar disorder. These are novel, intriguing directions for immunological research. Schizophrenia affects approximately 1% of the population and is characterized by positive symptoms, such as hallucinations and delusions, and negative symptoms, namely social withdrawal and lack of an emotional response. There’s no clear cut factor which causes schizophrenia but there are several genetic factors and prenatal effects. For example, there is increasing evidence that bacterial and viral infections which may occur in utero may have lasting effects on the developing fetus. Any sort of maternal immune response may lead to the production of cytokines in the mother which may cross the placenta and even the infant’s blood-brain barrier, leading to neurodevelopmental problems which may present as Schizophrenia. On the other hand, bipolar disorder affects roughly 2% of the population and is characterized by drastic mood swings. Previous research in both disorders has revealed heightened cytokine levels in both.

A New Take on the Importance of Memory

When you hear the word memory your initial thought may be to think of your brain.  However, the memory of cells plays an integral role in other systems of our bodies as well. Memory is crucial to the immune system’s ability to efficiently fight off infections.  Our bodies are miraculously able to generate antibodies against viruses while maintaining anti-viral antibody secreting cells to protect us from future attack by the same virus. While antibodies we make span a month, they retain the means of reproducing them for a lifetime (3).

In 1796, Edward Jenner’s noted that dairymaids and farmers lacked the smallpox that was disfiguring and killing whole villages. Cowpox during this time suffered from a similar disorder, cowpox, in which cattle experienced similar but less severe symptoms than humans (3). He exposed an 8-year-old boy first with fluid from an infected cow then two months later he inoculated the boy with smallpox. Sure enough, the boy’s immune system was able to remember how to fight the infection (3). This experiment, although clearly unethical, proved to be the first successful vaccination that would lead to the development of future vaccinations for a plethora of viruses. Jenner paved the way for future scientists to build off his idea of weakening pathogens in the laboratory to inoculate patients with in order to protect them from future exposure to that pathogen.  Today scientists continue to build off of this demonstration with the intent to better understand the cellular and molecular mechanisms governing this profound observation and experiment. 

Dendritic Cells Directly Engage Cancer

As members of the Colgate community know, especially in light of the recent passing of student Vic Krivitski ’12, cancer affects everyone’s life. Less apparent are the specific ways in which the immune system acts to mitigate cancer. To elucidate these mechanisms, a recent study in the Journal of Immunology investigates the role dendritic cells (DCs) play in killing cancer cells.

Cancer is a condition of uncontrolled cell growth. Not only are cancer cells good at promoting their own proliferation, but also they are proficient at avoiding the immune system. DCs are immune cells that have two characteristic functions, both of which can be thwarted in the presence of cancer (1). Typically, DCs act as antigen presenting cells (APCs), presenting antigens, pieces of pathogens, to lymphocytes to activate them. They can also secrete cytokines, signal molecules, that tell other cells to combat pathogens. Less well understood is DCs’ ability to act as killer DCs (KDCs), by directly engaging pathogens, and how this function is affected by cancer.

Larmonier and Bonnotte et. al. attempt to enhance the understanding of human-derived KDCs (hKDCs). KDCs have been examined previously in rats, mice, and humans (2,3,4) but this investigation provides finer details of hKDCs’ effective activation, mechanism for inducing cancer cell death, and ability to retain characteristic DC function.

hKDCs were prepared by exposing monocyte-derived DCs from cancer-free and stage IV cancer participants to low concentrations of an activating molecule, LPS. These hKDCs were found capable of killing several tumor lines (including HeLa) and reducing cancer cell viability up to 80%. This is a particularly exciting result because DCs derived from cancerous environments were found to be as effective as those from cancer free environments.

The mechanism for cancer cell death was elucidated via several experiments. ESR spectroscopy, which measures free radicals, showed that hKDCs produce reactive oxygen species (ROS). Decreased anti-tumor activity in the presence of FeTPPS, a free radical inhibitor, confirmed this result. When cancer cells and hKDCs were separated by a semi-permeable membrane, decreased anti-tumor behavior was observed suggesting that hKDCs kill cancer cells via direct cell-cell contact. Additionally, a staining experiment that allowed visualization of the dying cells as well as the death of certain apoptosis-resistant cancer cells suggests that the cells die by necrosis (catastrophic cell death) rather than apoptosis (programmed cell death). This, too, is promising because cancer cells are particularly adept at avoiding apoptosis, so a treatment that includes a necrotic mechanism might be effective against these cells.

Furthermore, the authors demonstrate that hKDCs retain their original DC functions: they are still able to present antigens (even those from cancer cells they kill themselves!) and produce cytokines. These promising results are not problem free and will require further study. hKDCs’ ability to kill certain non-cancerous cells requires an extensive investigation of the interactions between hKDCs and healthy cells. (It is important to note, however, that T lymphocytes were not killed by hKDCs. In fact, hKDCs produce cytokines that help T lymphocytes resist death.) Similarly, the mechanism of cell death itself is a danger to healthy cells, because necrosis releases dangerous toxins. Nevertheless, this study makes strides in understanding the relevancy of hDKCs for potential cancer treatments and may aid in the development of such treatments.

Reference: Lakomy, D., Janikashvili, N., Fraszczak, J., Trad, M., Audia, S., Samson, M., Ciudad, M., Vinit, J., Vergely, C., Caillot, D., et al. 2011. Cytotoxic dendritic cells generated from cancer patients. J. Immunol. 187(5): 2775-82.

Other Citations:

(1) Brown, M.P., Diener, K.R., Fraser, C.K., and Hayball, J.D. 2010. Unraveling the complexity of cancer immune system interplay. Expert Rev. Anticancer Ther. 10: 917.

(2) Fraszczak, J., Trad, M., Janikashvili, N., Cathelin, D., Lakomy, D., Granci, V., Morizot, A., Audia, S., Micheau, O., Lagrost, L., et al. 2010. Peroxynitrite-dependent killing of cancer cells and presentation of released tumor antigens by activated dendritic cells. J. Immunol. 184: 1876–1884.

(3) Chauvin, C., Philippeau, J. M., He ́mont, C., Hubert, F. X., Wittrant, Y., Lamoureux, F., Trinite, B., Heymann, D., Re ́dini, F., and Josien, R. 2008. Killer dendritic cells link innate and adaptive immunity against established osteosarcoma in rats. Cancer Res. 68: 9433–9440.

(4) Hill, K. S., Errington, F., Steele, L. P., Merrick, A., Morgan, R., Selby, P. J., Georgopoulos, N. T., O’Donnell, D. M., and Melcher, A.A. 2008. OK432- activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions. J. Immunol. 181: 3108–3115.