Signals Affecting Memory CD8+ T-cell Response - Essay Example

Signals Affecting Memory CD8+ T-Cell Response & Improvement of Vaccine Efficacy XYZ of so and so Signals Affecting Memory CD8+ T-Cell Response & Improvement of Vaccine Efficacy Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. The lymphocytes are further classified as the B lymphocytes (B Cells) and the T lymphocytes (T Cells). B cells are not only produced but also mature in the bone marrow. On the other hand the precursors of the T cells leave the bone marrow and their maturation takes place in the Thymus gland. Each T or B cell is specific for a particular antigen. Most of the T cells in the body belong to one of two subsets. The presence of one or the other of two glycoproteins makes them distinguishable as CD4 and CD8 type of T cells. The CD8+ T cells bind epitopes that are part of class I histocompatibility molecules. Almost all cells of the body express class I molecules. These cells have the role of recognizing antigens on the surface of a virus infected cell, binding to the cell ultimately destroying it (See Fig. I). Fig. I Site of action of CD8+ Cells Role of Cd8+ T Cells in Immunonotherapy Recent research in immunotherapy has lead to an understanding that by enhancing certain immune responses it might be possible to develop better approaches to treat allergic and infectious diseases as well as aid in developing better vaccines (Bardi J.S., 2006). CD8+ T cells play an important role in eliciting immune response to invading pathogens and other noxious stimuli. These cells are also known as cytotoxic T cells and it has recently been found that their movement to the site of action is not random but guided by chemical signals released from other cells. Initially the CD8+ T cells are activated and mobilized in the lymph nodes. Once activated, they roam throughout the body and destroy cells infected with bacteria and viruses. The whole process is known as cell mediated immunity. Once the CD8+ cells encounter an infected cell, they release destroy the cell membrane and the protein content of the infected cell by releasing a plethora of lytic substances and concurrently produce molecules which help activate other immune cells. After the initial infection has been dealt with, some of these CD8+ T cells keep circulating inside the body as memory cells which have specificity for the same pathogen if reinfection occurs. These memory cells are the key factors on which newer vaccination strategies are under current intensive research. There are a number of other factors which are responsible for the activation of CD8+ cells to sustain as memory cells within the lymph node. Inside the lymph nodes a combination of physical and chemical cues guide these cells towards the sites of activation. For the CD8+ T cells to be activated it must encounter the target antigen first and this encounter is made possible when the antigen is presented on the surface of another immune system cell known as the dendritic cell aided by helper T cells. The CD8+ cells carry a unique receptor protein on their surface called the T-Cell Receptor which has high specificity for the foreign antigen. The movement of the CD8+ cells towards the activation sites is under the influence of chemokines (F Castellino et al, 2006) produced by other cells towards which these cells move by developing and expressing specific receptors. The two important chemokines CCL3 and CCL4 are produced by the dendritic cells with assistance from the helper T cells. Once activated the CD8+ cells expand into a large population of active clones which handle the infection inside the body. According to Hinrichs C.S., et al (2006), the differentiation of CD8+ cells is a crucial determinant of their ability to handle infection. This differentiation is carried out under the influence of signals from T-Cell receptors, co-stimulatory molecules and cytokine receptors. These induce epigenetic changes that program gene expression patterns in the CD8+ cells which govern their progressive differentiation and lineage commitment decisions in the future. After dynamic interaction with the Antigen Presenting Cells (APCs), the CD8+ cells there is a generation of cells which have diverse phenotypic and functional characteristics. Although many, the two main categories in which these differentiated cells have been divided are the ‘Effector Cells’ TEFF and the ‘Memory Cells’ TM. The former are highly cytolytic due to the expression of cytolytic molecules like perforin, granzymes, interferon, tumor necrosis factor and FAS ligand. (Kaech S.M. et al, 2002 & Appay V. et al, 2004) The memory cells have two subsets called ‘Effector Memory’ cells (TEM) and ‘Central Memory’ cells (TCM). Memory CD8+ T cells are intermediates in the progressive differentiation pathway. It has been proposed that memory stem cells might represent the earliest antigen-experienced cell population to emerge in the CD8+ T-cell differentiation pathway. An early differentiation is vital for T cell efficacy as progressive differentiation leads to lesser ability to encounter infective cells although late effector cells have shown high cytolytic activity in vitro. (Kaech S.M et al, 2002) Therefore there is a need for direction of the early CD8+ T cell differentiation to generate early effectors which are programmed for optimal immune function. Inputs from T-cell receptors, cytokine receptors and co stimulatory receptors program CD8+ T cells. Advances have been made in identifying the master regulator transcription factors that govern T-cell differentiation. These can be the sites for manipulation for producing better immunotherapy and vaccines. Impact on Vaccine Developmental Strategies Killing of the cells harboring invading pathogens by the CD8+ T cells is affinity dependant and requires direct contact between the CD8+ cell and the its target for several minutes to an hour after which the CD8+ cell remains intact for additional killing (Robinson H.L & Amara R.R., 2005). According to them the goal of T cell vaccines is to generate long-lived memory CD8+ cells capable of recognizing and rapidly expanding to combat an infection. CD8+ T cells recognize peptides that are 8−11 amino acids long (epitopes) presented by major histocompatibility complex (MHC) class I antigens processed from foreign proteins. An example of MHC Class I antigens are the human leukocyte antigens (HLA). Protective CD8 cells can target any region of any internal or external microbial protein that can undergo class I presentation. Invading pathogens undergo T cell escape by mutating a target epitope so that it is no longer recognized by a responding CD8+ T cell (Goulder & Watkins, 2004). This is a major hurdle in T cell based vaccine production. In order to minimize microbial escape from a T cell response, vaccine inserts that have sufficiently large multiple epitopes ideally greater than 2000 amino acids are used. A second limitation of T cell vaccines is the potential for T cells to become exhausted by high levels of persisting antigen (Wherry E.J. et al, 2003). For a successful T cell mediated protection low-level CD8+ memory responses that are only minimally evolving in response to a contained infection are desirable. Efforts in achieving these desirable characteristics have begun only very recently. According to latest research Moss R.B. & Salk P.L. (2003) have suggested that CD4+ T cells play a critical role in nurturing CD8+ memory cells which are more effective in controlling viral replication. Therefore immunization strategies should be directed towards the induction of both CD4+ and CD8+ generation. The role played by other immune cells has to taken into account as the whole process is dynamic and controlled by multiple signals. This idea has been supported by Ekkens M.J. et al (2006) who have highlighted the role played by CD4 Th cells presence during the initiation stage of the immune response. Their study confirmed the role played by Th1 and Th2 cells in enhancing the primary and long lived memory CD8+ cell responses. Another factor influencing the generation of memory CD8+ cells i.e. the levels of epitope has been investigated by Wherry J.E. et al (2002). The study was conducted using a low, high and excessive level of epitopes in an experimental viral infection and it was found that at low levels there was a small epitope specific burst resulting in a low memory cell pool. This was enhanced significantly at high levels but at excessive level there was drastic reduction in the memory cell population. The study demonstrated successfully that epitope levels during primary CTL (Cytotoxic T Lymphocytes.) stimulation can be a major determinant of epitope-specific T cell memory size. Kolumam et al (2005) have highlighted the role of yet another factor, the Type I Interferon in its role on CD8+ cells on clonal expansion and memory formation. They demonstrated a loss of greater than 99% in the ability of the CD8+ cells to expand and generate memory cells when they were not in contact with Interferon I. They inferred that Interferon I signaling is a critical factor for the generation of effector and memory cells in response to infection. Boer R. J.D. (2007) has highlighted the failure of some of the tried strategies of prophylactic vaccination by boosting specific CD8+ cells in simian immunodeficiency virus experimental infection. According to him the time lag which these memory cells take to achieve high target/effector ratio and reach the primary site of action is too much and the invading pathogen dominates. This leads to vaccination failure. Thus signals that shape the characteristics of the memory CD8+ cell are multifarious and complex and the development of T cell based vaccines will have to face many hurdles as yet to come up with an effective vaccine but the current intensive research in this area is both invigorating and exciting. References Appay V, Rowland-Jones SL. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol. 2004; 16:205–212. Bardi Jason Socrates Chemical Guidance of T Cells Leads to Immunologic Memory and Long- Term Immunity National Institute of Health U.S. Department of Health and Human Services http://www.niaid.nih.gov Boer Rob J. De Understanding the Failure of CD8+ T-Cell Vaccination against Simian/Human Immunodeficiency Virus J Virol. 2007 March; 81(6): 2838–2848 Castellino F et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction. Nature DOI: 10.1038/nature04651 (2006). Ganesh A. Kolumam, Sunil Thomas, Lucas J. Thompson, Jonathan Sprent, and Kaja Murali- Krishna Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection JEM, Volume 202, Number 5, 637-650 Goulder, P.J. & Watkins, D.I. HIV and SIV CTL escape: implications for vaccine design. Nat. Rev. Immunol. 4,630−640 (2004) Harriet L Robinson & Rama Rao Amara T cell vaccines for microbial infections Review Nature Medicine 11, S25 - S32 (2005) Hinrichs Christian S , Gattinoni Luca , and Restifo Nicholas P Programming CD8+ T cells for effective immunotherapy Curr Opin Immunol. 2006 June; 18(3): 363– 370 http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/B_and_Tcells.html Fig. 1 Courtsey. Kaech SM, Hemby S, Kersh E, Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell. 2002;111:837–851 Kaech S.M., Wherry E.J., Ahmed R. 2002. “Effector and memory T-cell differentiation: implications for vaccine development.” Nature Rev. Immunol. 2:251-62. Melinda J. Ekkens, Devon J. Shedlock, EuiHye Jung, Amy Troy, Erika L. Pearce, Hao Shen, and Edward J. Pearce Th1 and Th2 Cells Help CD8 T-Cell Responses. Infection and Immunity, May 2007, p. 2291–2296 Moss Ronald B. and Salk Peter L. CD8+ memory T cells require CD4+ T cell help: Implication for therapeutic and preventive HIV vaccines AIDScience Vol. 3, No. 15, 2003 Wherry, E.J., Blattman, J.N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911−4927 (2003). Wherry E.J., McElhaugh M.J., Eisenlohr L.C. 2002. “Generation of CD8 (+) T cell memory in response to low, high, and excessive levels of epitope.” J. Immunol. 168:4455-61. Read More