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Biomedical subjects

George Kassiotis

Publications and source records attributed to George Kassiotis.

16 recordsLinked to original sources
PubMed2025

Evolution of antiviral host defenses against a backdrop of endogenous retroelements.

Mammalian hosts deploy a multitude of germ line-encoded mechanisms to detect and restrict virus infection. These mechanisms must avoid pathological responses to endogenous retroviruses and other endogenous retrotransposable elements (RTEs)-viruses and viruslike genomic parasites that have invaded the host germ line and are passed down the generations as host genes. Although the location, specificity, and sensitivity of innate pattern recognition receptors and restriction factors are tuned to facilitate discrimination of infecting viruses from those that are part of self, immune cross-reactions do occur. The RTE viral heritage may, therefore, compromise the ability of the host to respond to virus infection without risking pathology. Nevertheless, RTEs have the potential to be co-opted as an alarm amplification system, to be repurposed as antiviral factors, and to contribute to the evolution of antiviral genes.

Animals↗
PubMed2025

Tracking Nongenetic Evolution from Primary to Metastatic ccRCC: TRACERx Renal.

While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.

Journal Article↗
PubMed2006

Functional specialization of memory Th cells revealed by expression of integrin CD49b.

Infection or immunization induces heterogeneous memory T cell subsets, but their origin and protective value against infection are unclear. In this study, we report the functional characterization of two memory Th subsets, defined by expression of integrin CD49b. Stable CD49b expression is induced in up to one-half of all memory Th cells. More importantly, the CD49b- and CD49b+ subsets display distinct helper activities, typified by the production of IL-10 and TNF-alpha, respectively. Although the inflammatory properties of the CD49b+ subset are protective against intracellular bacterial infection, they are associated with immunopathology in acute viral infection. Modulation of the CD49b-defined memory Th subsets may provide infection type-specific interventions, where either enhancement of the inflammatory response or reduction of immunopathology is essential.

Animals↗
PubMed2006

Onset and progression in inherited ALS determined by motor neurons and microglia.

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non-cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.

Amyotrophic Lateral Sclerosis↗
PubMed2006

CD4+ memory T cells: functional differentiation and homeostasis.

CD4+ T cells are central regulators of both humoral and cellular immune responses. There are many subsets of CD4+ T cells, the most prominent being T-helper 1 (Th1), Th2, Th-17, and regulatory T cells, specialized in regulating different aspects of immunity. Without participation by these CD4+ T-cell subsets, B cells cannot undergo isotype switching to generate high-affinity antibodies, the microbicidal activity of macrophages is reduced, the efficiency of CD8+ T-cell responses and CD8+ T-cell memory are compromised, and downregulation of effector responses is impaired. It therefore stands to reason that memory CD4+ T cells are likely to fulfill an important facilitator role in the maintenance and control of protective immune responses. This review discusses some issues of importance for the generation of memory CD4+ T cells and focuses in particular on their heterogeneity and plasticity, with respect to both phenotypic characteristics and function. Finally, we discuss a number of factors that affect long-term maintenance of memory CD4+ T cells.

Animals↗
PubMed2005

Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis.

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin Ags leads to demyelination and paralysis. To investigate which molecules are crucial for the pathogenesis of EAE, we specifically assessed the roles of the death receptors Fas and TNF-R1. Mice lacking Fas expression in oligodendrocytes (ODCs) were generated and crossed to TNF-R1-deficient mice. To achieve specific deletion of a loxP-flanked fas allele in ODCs, we generated a new insertion transgene, expressing the Cre recombinase specifically in ODCs. Fas inactivation alone as well as the complete absence of TNF-R1 protected mice partially from EAE induced by the immunization with myelin ODC glycoprotein. The double-deficient mice, however, showed almost no clinical signs of EAE after immunization. Histological analysis revealed that demyelination was suppressed in CNS tissue and that lymphocyte infiltration was notably reduced. We conclude that the death receptors Fas and TNF-R1 are major initiators of ODC apoptosis in EAE. Although only moderate reduction of lymphocyte infiltration into CNS tissue was observed, the absence of these receptors appears to confer protection from demyelination and development of clinical disease.

Animals↗
PubMed2005

A major role for memory CD4 T cells in the control of lymphopenia-induced proliferation of naive CD4 T cells.

In a state of lymphopenia, naive and memory CD4 T cells compete with each other for expansion at the expense of naive T cells. This competition prevents the proliferation as well as the phenotypic and functional conversion of naive T cells to "memory-like" T cells and may consequently prevent immune pathology frequently associated with lymphopenia-induced proliferation of naive cells. However, in T cell replete mice, memory T cells do not compete with naive T cells, indicating independent homeostatic control of naive and memory CD4 T cells in conditions that do not involve profound lymphopenia. Moreover, within the memory compartment, subsequent generation of new memory T cells precludes the survival of memory-like T cells. Thus, memory T cells have a major role in the control of lymphopenia-induced proliferation of naive cells because they inhibit both the generation of memory-like T cells and their persistence within the memory compartment.

Adoptive Transfer↗
PubMed2004

Anatomical heterogeneity of memory CD4+ T cells due to reversible adaptation to the microenvironment.

The memory T cell pool is characterized by a substantial degree of heterogeneity in phenotype and function as well as anatomical distribution, but the underlying mechanisms remain unclear. In this study we confirm that the memory CD4(+) T cell pool in wild-type and TCR-transgenic mice consists of heterogeneous subsets, as defined by surface marker expression or cytokine production. Extralymphoid sites contain significant numbers of memory CD4(+) T cells, which are phenotypically and functionally distinct from their lymphoid counterparts. However, we show in this study that the phenotype of lymphoid and extralymphoid memory T cells is not stable. Instead, the unique properties of extralymphoid memory T cells are acquired upon migration into extralymphoid sites and are lost when memory T cells migrate back into lymphoid organs. Thus, at least some of the extralymphoid properties may represent a transient activation state that can be adopted by T cells belonging to a single memory T cell pool. Furthermore, such intermittent activation during or after migration into extralymphoid sites could provide an important signal, promoting the survival and functional competence of memory T cells in the absence of Ag.

Adaptation, Physiological↗
PubMed2004

Homeostasis and T cell regulation.

Homeostatic regulation of cell numbers is an important principle in biology. Mechanisms that function to maintain or re-establish homeostasis in the immune system include interactions among antigen-presenting cells, regulatory T cells and cytokines. The vital role that homeostatic regulation plays in maintaining a functionally intact immune system is illustrated by the perturbation of the peripheral T cell repertoire that occurs after lymphopenic incidents, which frequently provoke either exacerbated immune or autoimmune responses. Recent studies show that transient states of lymphopenia occur in viral infections and in the neonatal state and might be involved in the development of autoimmune diseases. On the positive side, lymphopenia-provoked T cell expansion might enhance weak immune responses and thereby aid the rejection of tumours or the elimination of parasites.

Animals↗
PubMed2004

CD4 T-cell memory.

CD4 T-cell memory is in some ways more enigmatic than CD8 T-cell memory. This is mostly due to the fact that CD4 T cells tend to expand far less in response to antigenic stimuli, thereby thwarting attempts at their detection during the course of an immune response. Nevertheless, there is a wide range of experimental models that have provided information regarding the survival and maintenance of CD4 memory cells, their functional capacities, their differentiation states and program of development following activation. The emerging picture is one of great versatility and functional heterogeneity as befits their central position within the immune system.

Animals↗
PubMed2003

Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells.

The requirements for survival and self-renewal of peripheral T cells and the nature of mechanisms controlling the size of the naive and memory pool are not completely understood. Here, we examine the involvement of the major histocompatibility complex (MHC) in survival and homeostatic expansion of naive and memory T cells. We show that the homeostatic behavior of naive T cell receptor (TCR)-transgenic T cells can be deduced by the expression levels of TCR and CD5, a negative regulator of TCR signaling. Both these factors determine the strength of TCR stimulation by MHC-derived signals. We further show that, similarly to naive T cells, MHC-derived signals influence the homeostatic expansion capacity of memory T cells under lymphopenic conditions. In contrast to naive T cells, however, memory T cells can reach a homeostatic equilibrium, in which survival/self-renewal of each clone is dissociated from their avidity for MHC-derived signals.

Adoptive Transfer↗
PubMed2003

Tumor necrosis factor-alpha regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathogenesis of several disorders and injuries in the central nervous system (CNS). Unlike IGF-I, which promotes CNS growth, TNF-alpha causes brain growth retardation and neural damage. Recently TNF-alpha has been shown to inhibit IGF-I signaling and actions in non-neural tissue. To investigate whether TNF-alpha deleteriously influences brain growth by altering the IGF-I system in vivo, we examined the expression of IGF-I, the type 1 IGF receptor (IGF1R) and IGF binding proteins (IGFBPs) in the brain of transgenic (Tg) mice with murine TNF-alpha overexpression. We show that overexpression of TNF-alpha reduces the weights of whole brain and all brain regions examined during development. In adult TNF-alpha Tg mice, cerebellum (CB) exhibited the greatest reduction in weight among the five brain regions examined, being approximately 77% of that in wild-type (WT) mice. IGF-I abundance was decreased in the CB, as well as in cerebral cortex and diencephalon, of TNF-alpha Tg mice. When compared to those in WT mice, CB IGF-I abundance in Tg mice was reduced by approximately 35%, approximately 45%, and approximately 40% at 2, 6, and 9 weeks of age, respectively. Of the IGFBPs studied the abundance of IGFBP-3 and IGFBP-4 was increased by 2-3.7-fold, and the abundance of IGFBP-5 was decreased by approximately 3-fold (as judged by Western immunoblot analysis). Histological analysis and immunocytochemical staining confirmed that TNF-alpha specifically increases IGFBP-3 and IGFBP-4 immunoreactivity, as well as that of the IGF1R, in radial glial and Purkinje cells. In addition, TNF-alpha alters CB cytoarchitecture, apparently by influencing granule cell migration. Our data indicate that TNF-alpha alters the expression of IGF-I system proteins in vivo, and suggest that altered expression of IGF-I system proteins may in part explain TNF-alpha deleterious actions on brain growth.

Age Factors↗
PubMed2003

T cell regulation as a side effect of homeostasis and competition.

We have previously hypothesized that maintaining a balanced peripheral immune system may not be the sole responsibility of a specialized subset of T cells dedicated to immune regulation, but also a side effect of normal competition for shared resources within an intact immune system. Here we show that regulatory activity is correlated with high homeostatic expansion potential, reflecting the avidity for self-peptide:MHC complexes. Monoclonal transgenic T cells with high homeostatic expansion potential and lacking characteristics previously associated with regulatory function were able to regulate wasting disease induced by transfer of a small number of naive CD45RB(hi) CD4 T cells into lymphopenic hosts. Self-regulatory function is also found in the naive polyclonal T cell repertoire depleted of CD25(+) T cells. T cells capable of preventing immune pathology, like the transgenic T cells, express higher than average levels of CD5, an indicator of avidity for self:MHC peptide complexes. We therefore propose that dysregulated expansion of potentially pathogenic T cells in a lymphopenic environment can be prevented by members of the naive T cell repertoire, irrespective of their specificity, as a side effect of their response to homeostatic and antigenic stimulation.

Animals↗
PubMed2002

Impairment of immunological memory in the absence of MHC despite survival of memory T cells.

The mechanisms by which immunological memory is maintained after infection or vaccination are still a matter of debate. Long-term survival of memory T cells does not require major histocompatibility complex (MHC) contact. We show here that compared with memory CD4+ T cells that maintain contact with MHC class II, memory CD4+ T cells deprived of MHC class II contact show distinct functional defects upon antigen re-encounter. Thus, in contrast to their survival, maintenance of the typical quality of memory T cells crucially depends on MHC-derived signals.

Animals↗