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T cell ageing: effects of age on development, survival & function

T cell ageing: effects of age on development, survival & function
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  T cell ageing: Effects of age on development, survival & function  Nasir Salam * , Sanket Rane * , Rituparna Das * , Matthew Faulkner  ** , Rupali Gund * , Usha Kandpal * , Virginia Lewis ** , Hamid Mattoo * , Savit Prabhu * , Vidya Ranganathan * , Jeannine Durdik  ** , Anna George * , Satyajit Rath *  & Vineeta Bal * *  National Institute of Immunology, New Delhi, India & **  Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA Received October 18, 2012 Age associated decline of the immune system continues to be a major health concern. All components of innate and adaptive immunity are adversely affected to lesser or greater extent by ageing resulting in an overall decline of immunocompetence. As a result in the aged population, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity. There is an increasing focus on the role of T cells during ageing because of their impact on the overall immune responses. A steady decline in the production of fresh naïve T cells, more restricted T cell receptor (TCR) repertoire and weak activation of T cells are some of the effects of ageing. In this review we summarize our present understanding of the effects of ageing on naïve CD4 T cells and potential approaches for therapeutic interventions to restore protective immunity in the aged population.Key words  Adaptive immunity - ageing - haematopoietic stem cells - innate immunity - TCR repertoire - T cells - thymic involution - transcription factors Review Article Indian J Med Res 138, November 2013, pp 595-608 595 Introduction  Higher organisms have evolved an elaborate defense mechanism against a variety of pathogenic organisms. The rst line of such defense is termed as the innate immune response as it is evolutionarily older, found in many more organisms, is non-specic in nature and depends upon recognition of highly conserved  pathogen associated molecular patterns (PAMPs) by a series of germline encoded pattern recognition receptors (PRRs). These receptors are expressed on a range of cells which respond to pathogenic threats by a number of means such as engulfment of pathogen, production of antimicrobial peptides and acid hydrolases, autophagy, production of highly reactive and oxidizing molecules like free radicals or reactive oxygen species (ROS). Together these mechanisms mediate the killing and clearance of organisms detrimental to the host 1 . A second defense mechanism evolved in jawed vertebrates and is now shared in humans. It is characterized by the  presence of a large array of anticipatory receptors that can recognize practically any kind of antigen 2 . These receptors are generated by rearrangement of genes and are expressed on specialized cells called lymphocytes 2 .  596 INDIAN J MED RES, NOVEMBER 2013 This kind of immune response is termed the adaptive immune response. Specicity to a particular antigen, generation of long-lived memory and tolerance to self-components are hallmarks of adaptive immune responses. The primary components of adaptive immunity are T and B lymphocytes, which srcinate in thymus and bone marrow, respectively and enter in circulation after maturation. The distinction of innate and adaptive response is not an absolute bifurcation of immunity as both these branches constantly cross communicate; naive T cells are primed by dendritic cells (DCs) which in turn secrete cytokines required for the recruitment and activation of innate immune cells like macrophages. Both these immune responses work together to protect the host from an invading  pathogen. The immune system in humans develops very early at the embryonic stage itself with the appearance of the rst haematopoietic stem cells (HSC) in embryonic yolk sac during the rst week of development, next migrating to liver and spleen, arriving in bone marrow eventually, which serves as primary centre of haematopoesis at birth and throughout the adult life of an individual 3 . Precursors of T lymphocytes migrate from the bone marrow and colonize the thymus. All the important events, such as gene rearrangement for generating diversity, development of functional lymphocyte and tolerisation to self-antigens take place in the bone marrow for B cells and in the thymus for T cells resulting in a fully competent lymphocyte repertoire. These lymphocytes stay in circulation throughout the adult life sensing non-self entities and mounting appropriate immune responses. As efcient as the immune system is in its multilayered approach in ghting pathogens, its efcacy decreases with ageing. It has been observed that intrinsic defects in cells of the immune system accumulate over a period of time manifesting themselves in the inability of the aged to mount an effective immune response against infectious disease and a heightened risk of developing autoimmune responses 4 . Age related immune dysfunctions are often described as ‘immunesenescence’ which can be a whole organismal effect or an effect on individual cells and its causes are wide ranging. From intrinsic defects such as thymic involution with age that leads to reduced thymic output in terms of naïve T cell numbers, reduction of B cell progenitors from bone marrow, oligoclonal expansion and accumulation of T cells because of chronic viral infections to an overall decline of regenerative capacity of the HSC with age or shortening of telomeres with successive cell division, many can be listed. All these factors contribute towards the phenomenon of immunesenescence 5,6 . Though age related changes on lymphocytes are well documented 7 , innate immune responses are also compromised in aged individuals 8 .  Effect of ageing on innate immunity  Many cell types of the innate immune system such as macrophages, DCs and neutrophils are adversely affected with advancing age. Macrophages/monocytes are present in all tissues and are the rst cells to encounter  particulate matter apart from neutrophils. It has been observed that macrophages from aged individuals have lower expression of surface molecules like major histocompatibility complex II (MHC-II) 9  and toll like receptors (TLRs) which could adversely impact their antigen presentation, produce poor levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α when stimulated with known agonists of TLR as compared to macrophages from young mice 10 . Other receptor driven functions like chemotaxis, phagocytosis and respiratory burst, essential for containing the pathogens are also compromised in the elderly 11 . Dendritic cells are another major component of the innate immune responses that are present in all tissues; these are characterized by their high phagocytic and antigen  processing and presentation capabilities. After antigen acquisition, DCs mature and migrate to the nearest lymph node by upregulating C-C chemokine receptor type 7 (CCR7) receptors. Once inside the lymph node these start priming naïve T cells. Cytokine secretion from DCs also determines to a signicant extent what differentiation pathway helper T cells would be directed to. Apart from macrophages, DCs are another cell type affected by ageing. Langerhans cells are DCs present in skin and their numbers decrease with increasing age 12 . DCs in aged individuals also have lower numbers of co-stimulatory molecules and lower  production of IL-12, though these retain their ability of antigen presentation 13 , indicating that some of the age related dysfunction observed in T cells could be related to changes in the effectiveness of the DC population in the aged. After an infection the rst cell type to inltrate the infected sites are neutrophils which are armed with a range of antimicrobial arsenal like superoxide, reactive nitrogen intermediates, antimicrobial peptides and degradative enzymes. These very short lived cells rapidly initiate an effective antimicrobial defense  before other specialized cells, e.g. , the lymphocyte can react to the threat. No change in their numbers has   been observed in the aged versus the young 14  but all functional aspects of neutrophils such as chemotaxis,  production of superoxide and their ability to respond to survival signals from granulocyte macrophage colony-stimulating factor (GM-CSF) are compromised leading to more apoptotic cells at the site of infection 15 . The  presence of these apoptotic cells at the site of infection could delay the resolution of infection resulting in  persistent inammation. Natural killer (NK) cells srcinate from common lymphoid progenitors that give rise to T and B lymphocytes; however, these do not express unique antigen receptors as expressed by either B cells or T cells. They mediate MHC-independent direct and rapid killing of virus-infected cells or tumour cells by the release of perforin and granzymes, and are identied by the expression of CD56 and CD16. It has  been observed that overall NK cell numbers increase with age, evident from an increase in the cytotoxic CD56 dim  population; however, their killer activity on a per cell basis decreases in the aged individuals and so does their ability to produce cytokines such as IL-8 and chemokines such as regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage inammatory protein (MIP)-1α, which might lead to a greater susceptibility of aged towards infection 16 .  Effect of ageing on adaptive immunity  B lymphocytes are crucial for humoral immunity. These cells srcinate in foetal liver or adult bone marrow from HSCs that give rise to common lymphoid precursors (CLPs). Some cells from CLPs differentiate into B cells under the inuence of the  bone marrow microenvironment by differential expression of transcription factors and cytokine receptors. The developing B cells undergo a series of stages characterized by the presence of cell surface markers and immunoglobulin gene recombination and are termed as pro-B cells, pre-B cells, immature-B cells, transitional-B cells and mature-B cells 17 . B cell development proceeds to the next stage only in the case of successful gene rearrangement of immunoglobulin genes; otherwise these are deleted. Their interaction with bone marrow stromal cells is very crucial for their development. Self-reactive immature-B cells are eliminated resulting in central tolerance of remaining B cells. B cells at immature-B cell stage expressing IgM on their surface migrate to the secondary lymphoid organs such as the lymph nodes or spleen. After encountering an antigen, either the B cells migrate to the medulla of lymph nodes, complete their differentiation and undergo class switching, becoming antibody secreting  plasma cells or migrate into a nearby follicle, forming a germinal centre by proliferating rapidly and undergoing somatic hypermutation, resulting in the selection of cells expressing immunoglobulins with an even higher afnity for previously encountered antigen (Figure A). Ageing affects B cell responses quantitatively, indicated  by reduced antibody production and qualitatively, evident in the production of lower-afnity antibodies 18 . The B cell pool in the aged decreases possibly because there is an overall decline in bone marrow output and reduction in numbers of HSCs committing to B cell lineage, resulting in a decrease of early B cell precursors in the aged mice (Figure B). For successfully clearing an infection, B cells undergo class switching, brought about by the help provided by T cells, whereby these can switch the production of surface IgM to IgG, IgE or IgA. Class switching produces essentially an antibody with the same specicity but with different effector function. It has been reported that both, the enzyme for class switching, activation-induced cytidine deaminase (AID) and E47, the transcription factor that controls its expression, are downregulated in aged murine B cells due to decreased mRNA stability 19 . Age related changes affect B cell population partly because of T cell dysfunction in the elderly but also because of the above-mentioned intrinsic defects in B cells and translate at a functional level in the compromised response of the elderly to vaccination and with the production of auto- reactive and lower afnity antibodies. The effects of ageing on T cells are more researched and documented than for any other cell  populations, primarily because these are the effectors and regulators of the immune response and because of thymic involution. This natural phenomenon reduces the output numbers of naïve T cells with increasing age. T cell precursors from bone marrow routinely seed the thymus where they undergo maturation and enter the periphery. Like B cells, T lymphocytes also undergo gene rearrangement for antigen receptors and extensive selection process where self-reactive T cells are deleted. Apart from the conspicuous effect of thymic involution on naïve T cells, it has been observed that ageing results in other functional defects as well: decreased T cell repertoire, decreased interleukin (IL)-2  production, and an increased memory T cell population due to low grade viral infection (Figure B) 20 . All these factors have a signicant negative impact on the immunity of the aged individuals.  SALAM et al  : T CELL AGEING 597  Generation and activation of T cells  T cell precursors arise from HSCs in bone marrow of adult or foetal liver. Thymic seeding progenitors (TSPs) arrive in the thymus in small numbers where upon their interaction with the thymic epithelium give rise to the earliest thymic progenitors (ETPs). ETPs develop gradually through successive stages of differentiation from CD4 - CD8 -  double negatives (DNs), to CD4 + CD8 +  double positives (DPs), to either CD4 +  or CD8 +  single positive (SPs) T cells restricting their lineage options at each stage. The development and schooling of T lymphocytes takes place in the thymus. The thymus is differentiated into an outer cortical region and an inner medullary region. One of the most important factors governing T cell development is the thymic microenvironment and the interaction of the T cell progenitors with thymic stromal cells. It is in the thymus that multipotent T cell progenitors lose alternative lineage differentiation capacity to become fully committed T cells.  Developmental stages of T cell progenitors is determined by thymic microenvironment   Depending on their developmental stage, T cell  precursors can be found in different thymic regions. ETPs enter the thymus from blood vessels near the cortico-medullary junction and under the inuence of CCR7 and CCR9 settle into the thymus 21 . These early ETPs are characterized as CD4 - CD8 - CD3 - CD44 + CD25 -  double negative (DN1) cells. These DN1 cells carry multi-lineage potential; and still retain the capability to differentiate into B cells, NK cells, DCs and T cells. A crucial factor that pushes DN1 cells exclusively towards a T cell fate is Notch signaling 22 . DN1 cells express the molecule, Notch1 and the corresponding ligand, delta-like ligand 4 (DLL4) is expressed by thymic epithelial cells. Induced deletion of Notch1 leads to complete block of T cell development leading to the ectopic development of immature B cells in the thymus 23 , indicating a central role of this molecule in T cell lineage commitment. However, little is known about the molecular mechanism by which Notch signaling induces this commitment. The cells now migrate deeper into the cortex, interaction with thymic epithelial cells (TECs) and broblasts leads to their differentiation into DN2 stage characterized byCD4 - CD8 - CD3 - CD44 + CD25 +  expression and the beginning of rearrangement of T cell receptor (TCR) gene locus 24,25 . DN2 cells carry the potential to differentiate into NK cells and DCs apart from T cell potential; however, these do not have any B cell potential left. Depending on IL-7 receptor expression these DN2 cells could be further subdivided as IL-7R  hi  and IL-7R  lo   that have the capacity to differentiate into γδ or αβ T cells, respectively 26 . DN2 cells go through a transition from an early DN2a (CD4 - CD8 - CD44 + CD25 + CD117 hi ) stage having the potential to give rise to DCs and NK cells to a late DN2b (CD4 - CD8 - CD44 + CD25 + CD117 int ) stage, completely losing the potential to differentiate into DCs and only retaining alternative NK cell lineage  potential 27 . Cells now migrate to the sub-capsular zone (SCZ) of the thymus maturing into DN3 cells dened as, CD4 - CD8 - CD3 - CD44 lo CD25 + . At this stage, nal commitment to T cell lineage occurs with no alternative developmental pathway left to explore. DN3 cells  begin to rearrange β-chain locus. A pre-T cell receptor is expressed at this stage on the cell surface comprising a TCRβ chain, a surrogate chain called pTα (pre T cell receptor α chain) and components of CD3 chains 28 . Cells that fail to productively rearrange their β-chain locus die. DN3 cells now migrate back towards the medullary cortex losing the expression of CD25 and  becoming DN4 cells characterized by CD4 - CD8 - CD3 - CD44 - CD25 -  expression. Signaling through the pre-TCR leads to the expression of CD4 and CD8 both on the surface of cells resulting into CD4 + CD8 + double  positive (DP) cells 29 . Rearrangement of the α-chain locus begins at this stage and DP cells start expressing low levels of the TCR complex. DP cells undergo  positive or negative selection by interacting with self-peptide MHC (pMHC) complex expressed on broblasts, DCs and TECs. Most cells fail to make it through, and die in the process. Relatively very few cells with intermediate avidity to self-pMHC survive that nally become CD4 - CD8 +  or CD4 + CD8 -  T cells 30 . Transcription factors  T cell lineage commitment is a sequential  process where at each stage, T cells lose the potential to differentiate into alternate lineages. Several transcription factors are activated and silenced during this process. One of these is BCL11b (B cell lymphoma 11b), a zinc nger transcription factor that is expressed at the DN2 stage and maintained throughout thymocyte development. BCL11b suppresses NK cell and myeloid lineages. Its deletion at the DN3 stage where thymocytes have committed to the T cell lineage lose expression of T cell lineage genes and start expressing NK cell lineage genes. This indicates the crucial importance of BCL11b transcription factor in the lineage commitment of thymocytes to a T cell fate 31 . Another essential transcription factor for T cell development is GATA3. Its role in initiating a Th2 598 INDIAN J MED RES, NOVEMBER 2013  effector programme is well established; however, GATA3 is also required for early T cell development in the thymus. It is expressed in ETPs and the expression continues until the DN3 stage after which it subsides, again becoming upregulated in single positive CD4 + T cells. GATA3 decient foetal liver cells give rise to very few ETPs, and no downstream T cell lineage  progenitors. GATA3 deciency has no effect on survival or proliferation, indicating that GATA3 most likely regulates differentiation of early T cell progenitors 32 . Expression of both these transcription factors BCL11b and GATA3 is induced by another transcription factor, T cell factor 1 (TCF-1) which is expressed in ETPs and is strongly upregulated by Notch signaling. TCF-1 deciency results in decreased thymic cellularity. Overexpression of TCF-1 leads to the induction of T cell lineage programme even in the absence of Notch signaling indicating its important role in early thymic development of T cell progenitors 33 . Chemokines  As evident from the above description, T cell development within the thymus is location specic. T cell  progenitors are recruited to the thymus depending on the expression of chemokine receptors where they migrate from the cortico-medullary junction to interior parts of the cortex to the sub-capsular zone and then traverse  back into the cortex. These intrathymic movements are controlled by the expression of chemokine receptors on T cell progenitors and their ligands expressed by thymic epithelial cells. The chemokine receptors crucial for settling of T cell progenitors into the thymus are CCR7 and CCR9. The ligands for CCR7 and CCDR9 are CCL19, CCL21, and CCL25, respectively, all of which are secreted in abundance by the thymic stromal cells. Adult mice lacking both CCR7 and CCR9 fail to recruit any T cell progenitors to the thymus 21,34 . Once inside the thymus, DN cells migrate towards the outer cortex, which is controlled by CXC chemokine receptor CXCR4 expression and its ligand CXC chemokine ligand CXCL12. CXCR4 deciency leads to the blockage of migration of thymocytes from the cortico-medullary junction to the cortex and, therefore, these fail to progress from DN1 stage to later stages of development 35 . Thymocytes undergo positive selection by their interactions with self-pMHC, which also results in the upregulation of CCR9 and CCR7 resulting in their migration back into the medulla. Chemokines play a very important role in localizing thymocytes in the different microenvironments within the thymus leading to their appropriate development into functional T cells.  Homeostatic maintenance of naïve T cell pool   Most of the thymocytes are deleted owing to their ability to bind self pMHC complex either too strongly or too weakly, thereby signicantly decreasing the chances for autoimmune responses later in their life time. The small pool of naïve T cells that survive are the cells with optimal binding ability to MHC. This T cell pool egresses the thymus and stays in constant circulation in the periphery searching for the presence of an appropriate ligand in the form of a peptide loaded MHC molecule. This naïve T cell pool stays constant through adult life despite thymic involution and transition of naïve T cells into memory T cells due to activation 36 . The survival and expansion of this naïve T cell pool in this stage is controlled by a number of factors, primary among these is their interaction with self-peptide loaded MHC and the presence of IL-7. The role of self-pMHC in maintenance of the naïve T cell pool has been reported in several studies. One such study has shown that CD4+ T cells engrafted into recombinant activating gene Rag-2 -/-  MHC II -/-  recipient mice gradually decline over a period of 6 months. This suggests that low level interactions of self-pMHC with TCR play a signicant role in long term survival and maintenance of the naïve T cell pool, probably by rescuing the cells from death 37 . Another study 38  found a different requirement for maintenance and proliferation of naïve and memory CD8+T cell population. Naïve T cells appear fastidious in their requirement for survival and proliferation on MHC I molecules, while memory CD8 T cells expand to a signicant extent even in the absence of all MHC I molecules. In contrast, Dorfman et al  39  have shown that naïve CD4 and CD8 T cells that interact with self-pMHC show activation of the TCR as evident by the partial phosphorylation of the TCRζ chain and the phosphorylation diminishes in absence of self-pMHC. However, such interactions were not found to be necessary for naïve T cell survival as evident  by their survival in MHC decient hosts for almost a month 39 . Despite contradictory initial claims, it is now well established that homeostatic proliferation requires low threshold of TCR activation that is provided by self-pMHC complex and full gain of effector function in such a situation will be detrimental for self. Thus, suboptimal induction of genes normally associated with TCR activation is sufcient for homeostatic  proliferation of naïve T cells, a unique gene pattern is neither observed nor seems to be required for such  proliferation in naïve CD8 T cells 40 . Another study indicated that when monoclonal transgenic CD4+ T cells were transferred at low frequency, they were better able SALAM et al  : T CELL AGEING 599
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