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SummaryWe have outlined the carefully orchestrated process of CD4 + T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4 + T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multi-faceted roles of CD4 + effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4 + T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza. Overview and historyOver the past decade, others and we have concluded that naïve precursor T cells must undergo many steps of division and differentiation before they acquire the effector functions necessary for their many regulatory activities (1). One of these activities is 'help' for B cells, which promotes B-cell isotype switching, somatic mutation, and differentiation in germinal centers to plasma cells and memory cells (2-4). Another key regulatory activity carried out by CD4 + T cells involves help for naïve CD8 + T cells to promote their optimum differentiation into cytotoxic effectors and memory cells and to support their maintenance (5-7). In addition, there are a host of other regulatory effects of CD4 + effectors on macrophages as well as other antigenpresenting cells (APCs). These CD4 + T-cell functions are mediated by surface coreceptors on the effector cells, including CD40L, CD28, cytotoxic T-lymphocyte antigen-4, etc., that interact with receptors on B cells, dendritic cells, macrophages, or other APCs, and by potent cytokines secreted by the CD4 + effectors upon recognition of antigen on APCs.CD4 + T-cell effectors represent a collection of distinct subsets characterized in part by their abilities to produce different patterns of cytokines. The two best characterized subsets are designated T-helper 1 (Th1), producing interferon-γ (IFN-γ), and Th2, producing interleukin-4 (IL-4), IL-5, and IL-13 as 'signature' cytokines. Recently, evidence has accumulated for a third . Most probably the APCs that stimulate the naïve CD4 + T cells are also the initial source of cytokines that imprint these subsets in situ (11). It is also increasingly accepted that the polarizing cytokines secreted by the APCs are dictated by the context of the antigen, be it from a pathogen or...

After allogeneic hematopoietic cell transplantation (HCT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse requires that calculated measures be taken to reduce GVHD pathology while retaining the graft-versus-leukemia (GVL) effect. We sought to determine whether donor CD4(+)CD25(+) regulatory T cells could control ongoing GVHD, thereby providing an initial window of time in which the alloreactive anti-host response is permitted to begin, with the intent of most effectively eliminating residual leukemia cells. Prevention of lethal GVHD by infusion of donor CD4(+)CD25(+) cells early after HCT (day 2) was achieved across a major histocompatibility complex barrier in the haploidentical C3H-->(B6xC3H)F(1) model. However, in vitro expansion of donor CD4(+)CD25(+) T cells, stimulated by recipient cells in the presence of high-dose interleukin-2, was required for successful regulation. In contrast, in the major histocompatibility complex-matched, minor histocompatibility antigen-disparate, CD8-mediated B10.BR-->CBA GVHD model, lethal disease could be completely prevented by a single infusion of freshly isolated donor CD4(+)CD25(+) cells administered as late as 10 days after HCT. Of importance, this late regulatory effect required only a 3:1 ratio of effector CD8:CD4(+)CD25(+) T cells, indicating a strong potential for the delayed infusion of CD4(+)CD25(+) cells to control GVHD across minor histocompatibility antigen barriers. Furthermore, this regulation did not interfere with complete and lasting donor engraftment of the hematopoietic compartment. Of most significance, the day 10 infusion of donor CD4(+)CD25(+) cells into CBA HCT recipients that had been challenged with the MMCBA6 myeloid leukemia cell line did not block an effective GVL response, despite reducing lethal GVHD. These results suggest that donor CD4(+)CD25(+) T cells infused soon after transplantation can ameliorate the development of GVHD without sacrificing a sufficient GVL effect.

Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/10/28/jimmunol.090129References

Elderly people are at higher risk for infections due to declining cellular and humoral immune responses. Central to this dysfunction is the reduced responsiveness of the naive CD4+ T cell compartment. Previous data from our laboratory suggest that although defects in the aged naive CD4+ T cell response are apparent in recent thymic emigrant populations, additional defects develop during extended post-thymic longevity in the periphery. To further investigate the factors that lead to aging defects, we took advantage of the OT-II TCR-transgenic (Tg) mouse model. We show that because of an apparent superantigen-mediated loss of naive Vβ5+ Tg CD4+ T cells from the periphery of aging OT-II mice, this compartment becomes enriched for cells of reduced post-thymic longevity, resulting in a frequency of recent thymic emigrants in aged mice that is similar to that of young mice. Purification and functional analysis of aged OT-II cells with reduced post-thymic longevity reveal that they have an age-associated decrease in expansion and IL-2 production in response to Ag in vitro. However, the in vivo expansion, IL-2 production, and cognate B cell helper ability of these cells are similar to those of cells from young mice. In contrast, T cells from aged HNT Tg mice demonstrate extended post-thymic longevity and exhibit severe defects in the same in vitro and in vivo models. These data support a correlation between the requirement for increased post-thymic longevity and the development of the most severe naive CD4+ T cell-aging defects.