Biomedical subjects

Joseph C Sun

Publications and source records attributed to Joseph C Sun.

8 recordsLinked to original sources

PubMed2026

Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability.

Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L + cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.

Animals↗

PubMed2006

Augmented IL-7 signaling during viral infection drives greater expansion of effector T cells but does not enhance memory.

IL-7 signals are crucial for the survival of naive and memory T cells, and the IL-7R is expressed on the surface of these cells. Following viral infection, the IL-7R is expressed on only a subset of effector CD8 T cells, and has been demonstrated to be important for the survival of these memory precursors. IL-7 message levels remain relatively constant during the T cell response to lymphocytic choriomeningitis virus, but a short-lived burst of GM-CSF is observed soon after infection. Retroviral expression of a chimeric GM-CSF/IL-7R, in which binding of GM-CSF by T cells leads to IL-7 signaling, allows for the delivery of an IL-7 signal in all effector T cells expressing the receptor. In mice infected with lymphocytic choriomeningitis virus, CD8 and CD4 T cells transduced with this chimeric receptor underwent an enhanced proliferative response compared with untransduced populations in the same host. Similarly, TCR transgenic CD8 cells expressing the chimeric receptor produced higher effector numbers during the peak of the T cell response to infection. Surprisingly, the enhanced proliferation did not lead to higher memory numbers, as the subsequent contraction phase was more pronounced in the transduced cell populations. These findings demonstrate that artificial IL-7 signaling during an infection leads to significantly increased Ag-specific effector T cell numbers, but does not result in increased numbers of memory progeny. The extent of contraction may be dictated by intrinsic factors related to the number of prior cell divisions.

Adoptive Transfer↗

PubMed2006

Developing and maintaining protective CD8+ memory T cells.

A critical aim of vaccine-related research is to identify the mechanisms by which memory T cells are formed and maintained over long periods of time. In recent years, we have designed experiments aimed at addressing two key questions: (i) what are the factors that maintain functionally responsive CD8+ memory cells over long periods of time, and (ii) what are the signals during the early stages of infection that drive the differentiation of long-lived CD8+ memory T cells? We have identified a role for CD4+ T cells in the generation of CD8+ T-cell-mediated protection from secondary challenge. While CD4+ T cells appear to play a role in the programme of CD8 memory, we find that they are also required for the long-term maintenance of CD8+ memory T-cell numbers and function. This property is independent of CD40-CD40L interactions, and we propose a role for CD4+ T cells in maintaining the ability of CD8+ memory T cells to respond to interleukin-7 (IL-7) and IL-15. By manipulating both the time course of infection and the timing of antigen presentation to newly recruited CD8+ T cells, we also demonstrate that the programming of effector and memory potential are at least partially distinct processes.

Animals↗

PubMed2004

CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection.

Immunization in the absence of CD4(+) T cell help results in defective CD8(+) T cell memory, deficient recall responses and diminished protective immunity. Here we investigated at what stage during the immune response to pathogen CD4(+) T cells are essential in the promotion of functional CD8(+) T cell memory. Memory CD8(+) T cell numbers decreased gradually in the absence of CD4(+) T cells despite the presence of similar numbers of memory cell precursors at the peak of the effector phase. Adoptive transfer of effector or memory CD8(+) T cells into wild-type or CD4(+) T cell-deficient mice demonstrated that the presence of CD4(+) T cells was important only after, not during, the early CD8(+) T cell programming phase. In the absence of CD4(+) T cells, memory CD8(+) T cells became functionally impaired and decreased in quantity over time. We conclude that in the context of an acute infection, CD4(+) T cells are required only during the maintenance phase of long-lived memory CD8(+) T cells.

Adoptive Transfer↗

PubMed2004

Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells.

CD8 T cells need CD4 T cells to develop into long-lived, functional memory cells that provide protection against pathogen rechallenge. We investigated whether signaling via CD40 expressed on the CD8 cells themselves is involved in this cooperation. In murine responses to Listeria monocytogenes and lymphocytic choriomeningitis virus, we found no evidence of any requirement for CD40-CD40 ligand interaction at this level. No differences were observed between CD40(-/-) and CD40(+/+) CD8 T cells that had matured in the same environment when comparing their expansion in a primary or secondary response, their contribution to memory, and their ability to enter nonlymphoid tissues such as the liver. Thus, we find no evidence that CD40 ligand-expressing CD4 T cells are required to activate CD40 on CD8 T cells directly for the full differentiation of the cytotoxic T cell response.

Animals↗

PubMed2004

The CD8 population in CD4-deficient mice is heavily contaminated with MHC class II-restricted T cells.

In experiments to study the impact of deficiency in CD4+ T cell help on the magnitude of CD8+ cytotoxic T cell response to pathogens, it was noted that in CD4 gene knockout mice, the CD8 population made significant responses to several nominally major histocompatibility complex (MHC) class II-restricted epitopes in addition to the expected responses to MHC class I-restricted epitopes. A similar response by CD8+ T cells to class II-restricted epitopes was not observed in wild-type mice, or in mice that had been acutely depleted of CD4+ T cells just before the immunization. Coincident with this unexpected response to class II-restricted epitopes, it was also observed that the CD8+ response to the class I-restricted epitopes was consistently lower in CD4-/- mice than in wild-type mice. Further experiments suggested that these two observations are linked and that the CD8 population in CD4-/- mice may contain a majority of T cells that were actually selected by recognition of MHC class II molecules in the thymus. These results have implications for understanding CD4 versus CD8 lineage commitment in the thymus, and for the practical use of CD4-/- mice as models of helper deficiency.

Animals↗

PubMed2003

Defective CD8 T cell memory following acute infection without CD4 T cell help.

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

Adoptive Transfer↗

PubMed2002

Positive selection of MHC class Ib-restricted CD8(+) T cells on hematopoietic cells.

Unlike conventional CD8(+) T cells, major histocompatibility complex (MHC) class Ib-restricted CD8(+) T cells show an activated phenotype in uninfected mice and respond rapidly to foreign invaders. The underlying factors that contribute to these differences are not well understood. We show here that the activated phenotype of MHC class Ib-restricted CD8(+) T cells was partially acquired as a result of interactions in the thymus and reflected an increased capacity to be selected via interactions with MHC molecules on hematopoietic cells. Using bone marrow-chimeric mice, we have shown that MHC class Ib-restricted, but not MHC class Ia-restricted, CD8(+) T cells specific for Listeria monocytogenes were efficiently selected when MHC class I was expressed only on hematopoietic cells. Thus, the distinct functional properties of MHC class Ib-restricted versus MHC class Ia-restricted CD8(+) T cells may result, at least in part, from the different ways in which they are positively selected in the thymus.

Animals↗