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. 2005 Nov;116(3):318-27.
doi: 10.1111/j.1365-2567.2005.02227.x.

Enhanced responsiveness to antigen contributes more to immunological memory in CD4 T cells than increases in the number of cells

John T Bates  1 , R Pat Bucy
Affiliations

Enhanced responsiveness to antigen contributes more to immunological memory in CD4 T cells than increases in the number of cells

John T Bates et al. Immunology. 2005 Nov.

Abstract

Although immunological memory is characterized by both an increase in the frequency of antigen-specific T cells and a qualitative change in the pattern of their subsequent response, it is not clear which of these components is more significant in the overall enhanced response to secondary stimulation. To address this question for the CD4+ T-cell response, T-cell receptor (TCR) Tg T cells were adoptively transferred to normal syngeneic mice that were immunized with the relevant peptide. After the initial expansion of TCR Tg T cells, the size of the subsequent memory population of T cells was approximately the same as the size of the starting population, independent of the number of TCR Tg cells initially transferred. This result was not caused by redistribution of memory cells into non-lymphoid tissues, although the relative frequency of antigen-specific T cells in these sites was increased after immunization. The fraction of the antigen specific TCR Tg cells that responded by production of either interleukin-2 or interferon-gammain vitro was substantially higher after immunization. Thus, the increased frequency of functionally responsive T cells was primarily caused by a higher fraction of responding T cells, rather than a substantial increase in the absolute number of antigen specific CD4+ TCR Tg T cells.

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Figures

Figure 1
Figure 1
Expansion and contraction of adoptively transferred CD4+KJ1.26+ cell populations in recipient BALB/c ByJ mice as measured by flow cytometry in (a) spleen and (b) lymph nodes. Cell transfers were performed on day −2 and mice were killed on day 0 (unimmunized) and on days 5, 10, and 30 following immunization with 100 µg of OVA peptide in adjuvant. Circles – 25 × 106 cell dose; triangles – 1 × 106; diamonds – 0·04 × 106. Error bars indicate the standard error of the mean.
Figure 2
Figure 2
Photomicrograph of lymph node sections stained with KJ1.26 on days 0, 5, and 30 following immunization. Mice received 0·04 × 106, 1 × 106 or 25 × 106 CD4+ KJ1.26+ cells. Equivalent expansion and contraction of the numbers of KJ1.26+ cells per square millimetre was observed in the spleen.
Figure 3
Figure 3
CFSE dilution profiles of CD4+ KJ1.26 + lymphocytes from the spleen on day 3 following immunization. 25 × 106– grey fill; 1 × 106– solid line; 0·04 × 106– dotted line.
Figure 4
Figure 4
Comparison of activation and memory marker expression by CD4+ KJ1.26+ lymph node cells from OVAp immunized (thick line) and KLH control immunized (thin line) mice 30 days following immunization. Modulation of activation and memory marker expression by CD4+ KJ1.26+ splenocytes was equivalent.
Figure 5
Figure 5
Photomicrograph showing KJ1.26+ cells in the small intestine, lung and liver in mice which received 1 × 106 CD4+ KJ1.26+ cells.
Figure 6
Figure 6
(a) KJ1.26+ cell numbers in spleen, lymph nodes, small intestine, Peyer's patches, lung, liver, and combined other compartments (salivary gland, kidney, heart, and skeletal muscle) on day 0 without immunization (black) and day 30 following immunization (unfilled). Asterisks indicate total populations sizes below the limit of detection for the respective compartment. Results are from four mice on day 0 and five mice on day 30. Adoptive transfer mice received 1 × 106 CD4+ KJ1.26+ cells. (b) KJ1.26+ cell number in the lymph nodes and lungs of adoptive transfer recipient mice that were immunized with OVAp in ME adjuvant or with OVAp in LPS. Results are from three mice for each condition.
Figure 7
Figure 7
Enhanced functional response in memory cells compared to naïve cells in adoptive transfer recipient mice that received 4 × 106 CD4+ KJ1.26+ cells. (a) KJ1.26+ cells composed approximately 1% of the total splenic CD4+ lymphocyte population. (b) Intracellular IFN-γ and IL-2 production by KJ+ CD4+ and KJ+ CD4– splenocytes from OVAp-immunized adoptive transfer recipient mice and unimmunized control mice following five hr in vitro stimulations. Plots are gated on the KJ1.26+ population.
Figure 8
Figure 8
The percentage of CD4+ KJ1.26+ cells which produce IL-2 (a) and IFN-γ (b) following in vitro stimulation with OVAp is greater in memory populations (hatched) than in populations of naïve cells (black fill). Relative contributions of increased cell number and increased fractional response to the ratio of memory to naïve responsiveness (c).
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