CD4+ T cell effectors can become memory cells with high efficiency and without further division

Hu, Hui; Huston, Gail E.; Duso, Debra K.; Lepak, Nancy M.; Román, Eulogia; Swain, Susan L.

doi:10.1038/90643

Cited by 169 publications

(180 citation statements)

References 45 publications

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“…One possibility is that persistence of a peptide on the class II molecule provides an advantage for stable CD4 memory generation and maintenance. Although it is known that antigen persistence is not required to generate memory cells (42)(43)(44)(45), it is possible that continued opportunities to engage the CD4 T cells agonist ligand provides some advantage in the quantity or quality of memory T cells (29,(46)(47)(48)(49). Also, engagement of CD4 T cells, particularly follicular helper T cells, with antigen-specific B cells in the germinal center may be most efficient and long-lived for stable peptide:class II complexes (23).…”

Section: Discussionmentioning

confidence: 99%

Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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Immunodominance refers to the highly selective peptide reactivity of T cells during an immune response. In this study, we tested the hypothesis that persistence of peptide:class II complexes is one key parameter that selects the final specificity of CD4 T cells. We found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion becomes strikingly aborted in the presence of competitive T cell responses to unrelated peptides. Our experiments revealed that for inhibition to occur, the competitive responses must be initiated by the same antigen presenting cell, and it is not because of competition for MHC binding. These studies not only provide an insight into the events that regulate competitive CD4 T cell priming in vivo, but also provide a previously undescribed conceptual framework to understand the parameters that select the final specificity of the T cell repertoire during pathogen or vaccine-induced immune responses.A ntigen presenting cells (APC) ingest antigens in peripheral tissues and, in response to inflammatory signals, migrate to lymph nodes (LNs), where they present peptide antigens bound to MHC class II molecules to recirculating CD4 T cells. The majority of T cells that are primed during an immune response are selectively skewed to one or a few of the many possible peptides from an antigen, resulting in a phenomenon known as immunodominance. Our laboratory has shown that an intrinsic biochemical property of the ligand recognized by the responding T cells, the kinetic stability of the peptide:MHC class II complexes, has the major role in both predicting and determining immunodominance (1). High-stability peptides elicit dominant responses, whereas low-stability peptides do not recruit detectable responses and are thus, ''cryptic'' (1). Selectivity in the repertoire of the presented peptide:class II complexes was shown to be modulated by DM editing in APC (2-4), and to be independent of the protein context in which those peptides resided (5).Recent findings describing the dynamic interactions of antigenbearing dendritic cells (DC) and T cells suggest that peptide off-rates from class II molecules may impact the immune response (6-8). The quality of signals received through the T cell antigen receptor (TcR) by peptides of different affinity for MHC class II has recently been suggested to regulate the fate and function of CD4 T cells (9, 10). Despite new methods that allow visualization of different phases of DC:T cell interactions to antigenic stimulus in vivo (11-18), the factors that contribute to efficient T cell activation and how the kinetic features of those interactions governs the fate of the responding T cells is still unknown. The decision for a T cell to ''stop'' and form long-lived contacts with a DC when scanning for cognate antigen may depend on multiple parameters, but antigen density (12) and peptide affinity for class II (19) have been shown to augment the frequency of prolonged DC:T cell contacts, increasing the efficienc...

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Section: Discussionmentioning

confidence: 99%

Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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“…Cells that produce IFN-␥ are by definition effector memory cells (33), whereas cells that produce IL-2 would include three subsets consisting of naive cells, effector memory cells (33), as well as Ag-experienced effector cells that have returned to a resting state (44). The selective reduction in the number of double-positive effector cells may be a consequence of HIV infection.…”

Section: Discussionmentioning

confidence: 99%

Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection

Boaz¹,

Waters

Murad

et al. 2002

The Journal of Immunology

221

155

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HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/μl. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-γ and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2+IFN-γ−) or IFN-γ alone (IFN-γ+IL-2−) did not differ between LTNPs and SPs. The decrease in p24-specific CD28+IL-2+ cells with a concomitant increase of p24-specific CD28−IL-2+ cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28−IL-2+ cells were evident in LTNPs and SPs, whereas the CMV-specific CD28−IL-2+ response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-γ+IL-2+ response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-γ+IL-2+ but not of IFN-γ+IL-2− CD4s correlated inversely with virus load. The Gag-specific IFN-γ+IL-2+ CD4 response also correlated positively with the percentage of Gag-specific IFN-γ+ CD8 T cells in these subjects. Accumulation of specific CD28−IL-2+ helpers and loss of IFN-γ+IL-2+ CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.

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“…Generation of Effectors, Rested Effectors, and Memory CellsTh1 and Th2 effectors and rested effectors were generated as described previously (15,17). Highly purified naïve cells (1.5 ϫ 10 5 /ml) from AND TCR Tg mice were cultured with mitomycin C (100 g/ml)-treated fibroblast APC expressing B7 and ICAM-1 (DECK.ICAM) (7.5 ϫ 10 4 /ml) and 5 M pigeon cytochrome c fragment, amino acids 88 -104 (PCCF).…”

Section: Methodsmentioning

confidence: 99%

“…We found that when in vitro generated CD4 ϩ T cell effectors are further cultured in the absence of antigenic stimulation, they revert to a resting state that phenotypically resembles memory cells (16,17). When we adoptively transferred these "rested effector" cells, they migrated mainly to lymphoid sites and efficiently developed into long lived memory cells, which persist indefinitely without the need for any further division (17). This raises the possibility that recruitment to non-lymphoid sites is restricted to highly activated effectors.…”

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confidence: 99%

Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation

Agrewala

Brown

Lepak

et al. 2007

Journal of Biological Chemistry

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Recent studies suggest that effector T cells generated by immune responses migrate to multiple non-lymphoid sites, even those without apparent expression of antigen or inflammation. To investigate the ability of distinct CD4؉ T lymphocyte subsets to enter and persist in non-lymphoid, noninflamed compartments, we examined the migration and persistence of naïve, effector, and rested effector CD4؉ T cells generated in vitro following transfer to nonimmunized adoptive hosts. Th1 and Th2 effectors migrated to both lymphoid and non-lymphoid organs (peritoneum, fat pads, and lung). In contrast, rested effectors and naïve cells migrated only to lymphoid areas. Adhesion molecule expression, but not chemokine receptor expression, correlated with the ability to enter non-lymphoid sites. Donor cells persisted longer in lymphoid than in non-lymphoid sites. When hosts with naïve and memory donor cells were challenged with antigen, effectors developed in situ, which also migrated to non-lymphoid sites. Memory cells showed an accelerated shift to non-lymphoid migration, in keeping with memory effector formation. These results suggest that only recently activated effector T cells can disperse to non-lymphoid sites in the absence of antigen and inflammation, and as effectors return to rest, they lose this ability. These data also argue that memory cells in lymphoid sites are longer lived and not in equilibrium with those in non-lymphoid sites.

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CD4+ T cell effectors can become memory cells with high efficiency and without further division

Cited by 169 publications

References 45 publications

Abortive activation of CD4 T cell responses during competitive priming in vivo

Abortive activation of CD4 T cell responses during competitive priming in vivo

Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection

Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation

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