As aging is associated with a decline in protective immunity to foreign pathogens, understanding how the immune system changes with age is important for the design of both therapeutic interventions and vaccines to treat infectious diseases in the elderly. Since CD4 T cells play a central role in mediating the response to foreign antigens, many studies have directly compared the function of young and aged CD4 T cells. However, during immune responses CD4 T cells do not function independently of the rest of the immune system, rather, they interact with other cell types and are exposed to different cytokines. The objective of this proposal is to study the context in which CD4 cells are activated, that is, the effect of the aged microenvironment on antigen-specific CD4 T cell responses. An adoptive transfer model will be employed in which CD4 T cell responses can be monitored in vivo. By transferring antigen-specific T cells into young and aged mice, the effect of the different microenvironments in which CD4 T cells function can be directly compared. By characterizing the transferred T cell population at different stages of the response, it will be possible to determine how the aged microenvironment effects T cell activation and expansion, activation- induced cell death, and memory T cell development. T cells from DO11.10 T cell receptor transgenic mice specifically recognize a peptide derived from ovalbumin (OVA) in the context of self-MHC class II molecules. These T cells can be adoptively transferred into BALB/c mice, and following immunization with OVA, the response of these T cells can be monitored.
The specific aims of this proposal are: (1) To characterize the rate and magnitude of CD4 T cell expansion in young and aged animals. Flow cytometry will be used to enumerate the number of OVA-responsive cells after immunization. Further, differences in the number of recovered T cells in young versus aged recipients will be related to the degree of cell growth or to levels of cell death. (2) To determine the role of antigen presenting cells in the aged and young microenvironment. The primary focus will be on young versus aged B cells and their ability to modulate T cell activation in vitro and in vivo. (3) To determine the role of pro-inflammatory cytokines in modulating activated T cell numbers in aged and young mice. Age-related changes in the basal and induced levels of these cytokines will be determined. Further, the effects of these cytokines on the in vivo CD4 T cell response will be determined by administering neutralizing antibodies in conjunction with adoptive transfer of T cells. These studies will further the understanding of the physiological basis of age-related changes that occur in the immune system, and may help explain the decline in protective immunity in the elderly.
| Mittler, James N; Lee, William T (2004) Antigen-specific CD4 T cell clonal expansion and differentiation in the aged lymphoid microenvironment. II. The memory T cell response is diminished. Mech Ageing Dev 125:59-68 |
| Mittler, James N; Lee, William T (2004) Antigen-specific CD4 T cell clonal expansion and differentiation in the aged lymphoid microenvironment. I. The primary T cell response is unaffected. Mech Ageing Dev 125:47-57 |
| Watson, Andrew R O; Mittler, James N; Lee, William T (2003) Staphylococcal enterotoxin B induces anergy to conventional peptide in memory T cells. Cell Immunol 222:144-55 |
| Lee, William T; Pasos, Gregory; Cecchini, Luiza et al. (2002) Continued antigen stimulation is not required during CD4(+) T cell clonal expansion. J Immunol 168:1682-9 |
