Precursor Frequency, Nonlinear Proliferation, and Functional Maturation of Virus-Specific CD4+ T Cells

Whitmire, Jason K.; Benning, Nicola; Whitton, J. Lindsay

doi:10.4049/jimmunol.176.5.3028

Cited by 75 publications

(112 citation statements)

References 69 publications

(157 reference statements)

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“…5A). Whitmire et al (19) have shown there are Ϸ100 GP61-specific naïve cells in B6 mice (19), and we found a similar number (160) after directly labeling total spleen and lymph node cells with IA b /GP61tet (Fig. S6).…”

Section: Memory Cells Either Generated By or Reactivated With Lymphocsupporting

confidence: 79%

“…2C). Because we did not collect every LN, and there may have been some naïve IA b /3K-specific cells in the blood, this may be an underestimate, but this number is similar to that found in the Tg cell experiment and to that described for T cells with other specificities (19)(20)(21). To set a level of background staining, we examined tetramer staining of naïve CD4 T cells from mice that had been primed with an optimal dose of 3KϩLPS 7-9 days earlier.…”

Section: Memory Cd4 Cells Expand Less Efficiently Than Naïve Cells To Agsupporting

confidence: 53%

“…2A). We and others (19,20) have found that Ϸ10% of cells survive after transfer. After the transfer of 500 cells, Ϸ50 would be expected to respond to a subsequent immunization, suggesting there are Ϸ50 naive IA b /3K specific cells in a mouse.…”

Section: Memory Cd4 Cells Expand Less Efficiently Than Naïve Cells To Agmentioning

confidence: 73%

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CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

MacLeod

McKee

Crawford

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFN␥. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFN␥ increased the proliferation of the memory cells.interferon gamma ͉ interleukin 2 ͉ proliferation ͉ LCMV ͉ recall

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Section: Memory Cells Either Generated By or Reactivated With Lymphocsupporting

confidence: 79%

Section: Memory Cd4 Cells Expand Less Efficiently Than Naïve Cells To Agsupporting

confidence: 53%

See 1 more Smart Citation

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

MacLeod

McKee

Crawford

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Initially, this was a surprising finding. However, the Ag-specific precursor frequency for naive T cells is ϳ1/1 ϫ 10 5 (100 cells/spleen) (68,69), a small population capable of significantly expanding and producing a sufficient protective adaptive immune response upon antigenic stimulation. This response ultimately leads to the survival of ϳ5% of the activated T cells (ϳ1 ϫ 10 5 cells) to serve as a memory pool after the contraction phase (69).…”

Section: Discussionmentioning

confidence: 99%

A Costimulatory Function for T Cell CD40

Munroe

Bishop

2007

The Journal of Immunology

100

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CD40 plays a significant role in the pathogenesis of inflammation and autoimmunity. B cell CD40 directly activates cells, which can result in autoantibody production. T cells can also express CD40, with an increased frequency and amount of expression seen in CD4+ T lymphocytes of autoimmune mice, including T cells from mice with collagen-induced arthritis. However, the mechanisms of T cell CD40 function have not been clearly defined. To test the hypothesis that CD40 can serve as a costimulatory molecule on T lymphocytes, CD40+ T cells from collagen-induced arthritis mice were examined in parallel with mouse and human T cell lines transfected with CD40. CD40 served as effectively as CD28 in costimulating TCR-mediated activation, including induction of kinase and transcription factor activities and production of cytokines. An additional enhancement was seen when both CD40 and CD28 signals were combined with AgR stimulation. These findings reveal potent biologic functions for T cell CD40 and suggest an additional means for amplification of autoimmune responses.

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“…These effects can be grouped into 2 broad categories: (a) those affecting pMHCI abundance on the surface of APCs and (b) the number, recruitment, and proliferative capacity of naive epitope-specific CTLps that can engage in the response (1,6). The latter set of parameters has been especially difficult to measure, particularly when the naive CTLps are physiologically generated "endogenous" responders rather than TCR-Tg precursors (7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

Gruta¹,

Rothwell²,

Cukalac³

et al. 2010

J. Clin. Invest.

145

211

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CD8 + T cell responses to viral infection are characterized by the emergence of dominant and subdominant CTL populations. The immunodominance hierarchies of these populations are highly reproducible for any given spectrum of virus-induced peptide-MHCI complexes and are likely determined by multiple factors. Recent studies demonstrate a direct correlation between naive epitope-specific CD8 + T cell precursor (CTLp) frequency and the magnitude of the response after antigen challenge. Thus, the number of available precursors in the naive pool has emerged as a key predictor of immunodominance. In contrast to this, we report here no consistent relationship between CTLp frequency and the subsequent magnitude of the immune response for 4 influenza virus-derived epitopes following intranasal infection of mice with influenza A virus. Rather, the characteristic, antigen-driven T cell immunodominance hierarchy was determined by the extent of recruitment from the available pool of epitope-specific precursors and the duration of their continued expansion over the course of the infection. These findings suggest possibilities for enhancing protective immune memory by maximizing both the size and diversity of typically subdominant T cell responses through rational vaccine design.

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Precursor Frequency, Nonlinear Proliferation, and Functional Maturation of Virus-Specific CD4+ T Cells

Cited by 75 publications

References 69 publications

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

A Costimulatory Function for T Cell CD40

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

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