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A fractal clonotype distribution in the CD8+ memory T cell repertoire could optimize potential for immune responses
UMass Chan Affiliations
Department of PathologyDocument Type
Journal ArticlePublication Date
2003-04-19Keywords
CD8-Positive T-LymphocytesClone Cells
Cloning, Molecular
Colony Count, Microbial
Complementarity Determining Regions
Cytotoxicity Tests, Immunologic
Epitopes, T-Lymphocyte
*Fractals
Genetic Vectors
HLA-A2 Antigen
Humans
Immunologic Memory
Influenza A virus
Lymphocyte Count
Models, Immunological
Peptide Fragments
Receptors, Antigen, T-Cell, alpha-beta
T-Lymphocyte Subsets
T-Lymphocytes, Cytotoxic
Viral Matrix Proteins
Amino Acids, Peptides, and Proteins
Cells
Genetic Phenomena
Hemic and Immune Systems
Pathology
Metadata
Show full item recordAbstract
The nature of CD8(+) T cell memory is still incompletely understood. We have previously reported that the response to an HLA-A2-restricted influenza-derived peptide results in a complex T cell repertoire. In this study we extend this analysis and describe the repertoire with more rigor. In one individual we defined 141 distinct T cell clonotypes on the basis of the unique DNA sequence of the third complementarity-determining region of the TCR beta-chain. The frequency distribution of the clonotypes is not what is expected of a normal distribution but is characterized by a large low-frequency tail. The existence of a complex population indicates a mechanism for maintaining a large number of Ag-specific clonotypes at a low frequency in the memory pool. Ranking the clonotypes allowed us to describe the population in terms of a power law-like distribution with a parameter of decay of approximately 1.6. If the repertoire is divided into subsets, such as clonotypes that use BJ2.7 or those whose third complementarity-determining region encodes the amino acid sequence IRSS, the clonotype frequencies could also be described by a power law-like distribution. This indicates a self similarity to the repertoire in which smaller pieces are slightly altered copies of the larger piece. The power law-like description is stable with time and was observed in a second individual. The distribution of clonotypes in the repertoire could be mapped onto a polygonal spiral using a recursive algorithm. Self similarity, power laws, and recursive mapping algorithms are associated with fractal systems. Thus, Ag-specific memory CD8 T cell repertoires can be considered as fractal, which could indicate optimized flexibility and robustness.Source
J Immunol. 2003 Apr 15;170(8):3994-4001.
DOI
10.4049/jimmunol.170.8.3994Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38237PubMed ID
12682227Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.170.8.3994
Scopus Count
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Dynamics of memory T cell proliferation under conditions of heterologous immunity and bystander stimulationKim, Sung-Kwon; Brehm, Michael A.; Welsh, Raymond M.; Selin, Liisa K. (2002-06-22)By examining adoptively transferred CSFE-labeled lymphocytic choriomeningitis virus (LCMV)-immune donor T cells in Thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(I:C), strikingly different responses of bona fide memory T cells were found in response to different stimuli. Poly(I:C) (cytokine) stimulation caused a limited synchronized division of memory CD8 T cells specific to each of five LCMV epitopes, with no increase and sometimes a loss in number, and no change in their epitope hierarchy. Homologous LCMV infection caused more than seven divisions of T cells specific for each epitope, with dramatic increases in number and minor changes in hierarchy. Infections with the heterologous viruses Pichinde and vaccinia (VV) caused more than seven divisions and increases in number of T cells specific to some putatively cross-reactive but not other epitopes and resulted in substantial changes in the hierarchy of the LCMV-specific T cells. Hence, there can be memory T cell division without proliferation (i.e., increase in cell number) in the absence of Ag and division with proliferation in the presence of Ag from homologous or heterologous viruses. Heterologous protective immunity between viruses is not necessarily reciprocal, given that LCMV protects against VV but VV does not protect against LCMV. VV elicited proliferation of LCMV-induced CD8 and CD4 T cells, whereas LCMV did not elicit proliferation of VV-induced T cells. Thus, depending on the pathogen and the sequence of infection, a heterologous agent may selectively stimulate the memory pool in patterns consistent with heterologous immunity.
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Attrition of virus-specific memory CD8+ T cells during reconstitution of lymphopenic environmentsPeacock, Craig D.; Kim, Sung-Kwon; Welsh, Raymond M. (2003-07-09)Viruses can cause a severe lymphopenia early in infection and a subsequent, lasting loss of pre-existing CD8(+) memory T cells. We therefore questioned how well virus Ag-specific memory CD8(+) T cells could reconstitute mice rendered lymphopenic as a consequence of genetics, irradiation, or viral or poly(I:C)-induced cytokines. In each case, reconstitution of the CD8(+) compartment was associated with limited division of virus-specific memory T cells and a reduction in their proportion. This indicates that foreign Ag-experienced CD44(high)CD8(+) memory T cells may respond differently to homeostatic signals than other CD44(high)CD8(+) cells, and that events inducing lymphopenia may lead to a permanent reduction in T cell memory.