Biomedical subjects

Marc K Jenkins

Publications and source records attributed to Marc K Jenkins.

At least 19 recordsLinked to original sources

PubMed2025

Guidelines for T cell nomenclature.

Advances in T cell biology have revealed heterogeneity among T cell populations that is not captured by existing general nomenclature. This issue has caused an ad hoc broadening of core T cell subset definitions and the invention of new subset designations that have not been uniformly delineated. To address this issue, in this Consensus Statement, we propose guidelines that serve three goals. First, they advocate that primary research reports define the experimental basis by which relevant subsets are designated in the methods section of each study. Second, they provide standardized definitions for existing subset designations in popular use, and common experimental criteria for defining each subset are noted. Last, they present an alternative 'modular nomenclature' paradigm. The newly proposed modular nomenclature eschews conceptualization of antigen-experienced T cells as belonging to a few idealized subsets, and the nomenclature instead simply indicates individual biological properties present in a T cell population with brief descriptors. Collectively, these guidelines intend to enhance transparency in the literature while facilitating clearer communication of findings and concepts to researchers, students and clinicians.

Terminology as Topic↗

PubMed2006

CD25+Foxp3+ regulatory T cells facilitate CD4+ T cell clonal anergy induction during the recovery from lymphopenia.

T cell clonal anergy induction in lymphopenic nu/nu mice was found to be ineffective. Exposure to a tolerizing peptide Ag regimen instead induced aggressive CD4(+) cell cycle progression and increased Ag responsiveness (priming). Reconstitution of T cell-deficient mice by an adoptive transfer of mature peripheral lymphocytes was accompanied by the development of a CD25(+)Foxp3(+)CTLA-4(+)CD4(+) regulatory T cell population that acted to dampen Ag-driven cell cycle progression and facilitate the induction of clonal anergy in nearby responder CD25(-)CD4(+) T cells. Thus, an early recovery of CD25(+) regulatory T cells following a lymphopenic event can prevent exuberant Ag-stimulated CD4(+) cell cycle progression and promote the development of clonal anergy.

Adoptive Transfer↗

PubMed2006

CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells.

We explored the relationship between the time of naive CD4+ T cell exposure to antigen in the primary immune response and the quality of the memory cells produced. Naive CD4+ T cells that migrated into the skin-draining lymph nodes after subcutaneous antigen injection accounted for about half of the antigen-specific population present at the peak of clonal expansion. These late-arriving T cells divided less and more retained the central-memory marker CD62L than the T cells that resided in the draining lymph nodes at the time of antigen injection. The fewer cell divisions were related to competition with resident T cells that expanded earlier in the response and a reduction in the number of dendritic cells displaying peptide-major histocompatibility complex (MHC) II complexes at later times after antigen injection. The progeny of late-arriving T cells possessed the phenotype of central-memory cells, and proliferated more extensively during the secondary response than the progeny of the resident T cells. The results suggest that late arrival into lymph nodes and exposure to antigen-presenting cells displaying lower numbers of peptide-MHC II complexes in the presence of competing T cells ensures that some antigen-specific CD4+ T cells divide less in the primary response and become central-memory cells.

Animals↗

PubMed2006

Naive and memory CD4+ T cell survival controlled by clonal abundance.

Immunity to a plethora of microbes depends on a diverse repertoire of naïve lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of naïve CD4(+) T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.

Adoptive Transfer↗

PubMed2005

In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance.

In normal B cell development, a large percentage of newly formed cells bear receptors with high levels of self-reactivity that must be tolerized before entry into the mature B cell pool. We followed the fate of self-reactive B cells expressing high affinity anti-hen egg lysozyme (HEL) Ag receptors exposed in vivo to membrane HEL in a setting in which the anti-HEL L chain was "knocked-in" at the endogenous L chain locus. These mice demonstrated extensive and efficient L chain receptor editing responses and had B cell numbers comparable to those found in animals lacking membrane Ag. BrdU labeling indicated that the time required for editing in response to membrane HEL was approximately 6 h. In mice transgenic for soluble HEL, anti-HEL B cells capable of editing showed evidence for both editing and anergy. These data identify receptor editing as a major physiologic mechanism by which highly self-reactive B cells are tolerized to membrane and soluble self-Ags.

Animals↗

PubMed2004

Indirect minor histocompatibility antigen presentation by allograft recipient cells in the draining lymph node leads to the activation and clonal expansion of CD4+ T cells that cause obliterative airways disease.

Ag recognition by OVA-reactive OT-II (I-Ab restricted) and DO11.10 (I-Ad restricted) TCR-Tg CD4+ T cells after heterotopic transplantation of OVA transgene-expressing tracheal grafts was examined as a model of minor histocompatibility Ag (mHAg)-induced chronic allograft rejection. In response to airway allotransplantation with grafts expressing the OVA transgene, these TCR-Tg CD4+ T cells expressed the activation markers CD69 and CD44, demonstrated evidence of blastogenesis, underwent multiple rounds of cell division leading to their clonal expansion in the draining lymph node, and proceeded to differentiate to a effector/memory T cell phenotype based on a reduction in the expression of CD45RB. These mHAg-specific TCR-Tg CD4+ T cells responded equally well to fully MHC-mismatched tracheas and to class II-deficient allografts, demonstrating that donor mHAg recognition by recipient CD4+ T cells does not rely on Ag presentation by donor-derived APC. The activation of mHAg-specific TCR-Tg CD4+ T cells after their adoptive transfer into recipient mice given MHC-matched, but mHAg-disparate, airway allografts was associated with their movement into the allograft and the near uniform destruction of the transplanted airway tissue secondary to the development of obliterative airways disease. These results demonstrate that an activation of mHAg-reactive CD4+ T cells in the draining lymph node by recipient APC that indirectly express graft mHAg-derived peptide/class II MHC complexes precedes responder T cell proliferation and differentiation, and leads to the eventual migration of these alloreactive T cells to the transplanted airway tissue and the promotion of chronic graft rejection.

Animals↗

PubMed2004

IL-1 acts on antigen-presenting cells to enhance the in vivo proliferation of antigen-stimulated naive CD4 T cells via a CD28-dependent mechanism that does not involve increased expression of CD28 ligands.

The basis of the adjuvant effect of IL-1 on the clonal expansion of Ag-specific CD4 T cells was measured in vivo using the TCR transgenic T cell adoptive transfer method. Injection of Ag plus IL-1 caused naive CD4 T cells to proliferate to a greater extent than did injection of Ag alone. The T cells had to express CD28 to experience the beneficial effect of IL-1 whereas the host had to express the type I IL-1R, raising the possibility that IL-1's adjuvant properties were related to induction of CD28 ligands on APC. Surprisingly, however, expression of CD28 ligands on DC and B cells was not affected by IL-1. Therefore, the adjuvant properties of IL-1 depend on a basal level of CD28 signaling but cannot be explained by enhanced CD28 signaling due to CD28 ligand induction.

Adoptive Transfer↗

PubMed2004

Primary induction of CD4 T cell responses in nasal associated lymphoid tissue during group A streptococcal infection.

CD4 T cells are important for development of long-term immunity to bacterial infections. Here we describe construction of a group A streptococcus (GAS) strain that expresses the model ovalbumin epitope (OVA) on its surface, and the use of this strain in adoptive transfer experiments to study CD4 T cell response to bacterial infection in nasal-associated lymphoid tissue (NALT), which was previously shown to be a specific target for GAS colonization. The OVA(+) GAS, but not the wild-type strain was shown to activate CD4 T cells in an antigen-specific manner both in vitro and in vivo. After intranasal infection of mice with this strain, OVA-specific CD4 T cells were first activated in NALT, which is functionally equivalent to human tonsils, rather than in the cervical lymph nodes. During localized infection, OVA(+) GAS induced rapid and prolonged activation of CD4 T cells at higher magnitudes in the NALT than in draining lymph nodes and spleen, where CD4 T cells underwent little or no activation. In contrast, systemic infection induced significantly higher activation of CD4 T cells in both lymph nodes and spleens, compared to when the infection was localized in NALT. Further investigation of cellular immune responses in NALT during GAS infection using adoptive T cell transfer, combined with the model antigen on the pathogen may ultimately shed light on mechanisms for failure of children to develop protective immune responses following streptococcal tonsillitis.

Adoptive Transfer↗

PubMed2004

In vivo antigen presentation.

Monoclonal antibodies specific for defined peptide-MHC complexes are now being used to physically detect T-cell receptor ligands. These reagents have resulted in the identification of the cells that present antigen in lymphoid and non-lymphoid tissues after various forms of antigen administration. In addition, recent advances in real-time imaging technology have begun to measure the rate and directionality of T-cell movement relative to antigen-presenting cells in lymph nodes, shedding light on the earliest events in T-cell activation in a physiological setting.

Adjuvants, Immunologic↗

PubMed2004

Visualizing the first 50 hr of the primary immune response to a soluble antigen.

Recently, static and dynamic imaging methods have produced the first glimpses of the interactions between antigen-specific T cells and peptide-MHC-bearing antigen-presenting cells in the lymph nodes. Using data from these experiments, we produced a numerically, spatially, and temporally scaled simulation of the first 50 hr of the primary T cell-dependent immune response. The simulation highlights how lymph node structure facilitates antigen presentation to rare, naive, antigen-specific CD4+ T cells.

Animals↗

PubMed2003

Visualization of the genesis and fate of isotype-switched B cells during a primary immune response.

The life history of isotype-switched B cells is unclear, in part, because of an inability to detect rare antigen-specific B cells at early times during the immune response. To address this issue, a small population of B cells carrying targeted antibody transgenes capable of class switching was monitored in immunized mice. After contacting helper T cells, the first switched B cells appeared in follicles rather than in the red pulp, as was expected. Later, some of the switched B cells transiently occupied the red pulp and marginal zone, whereas others persisted in germinal centers (GCs). Antigen-experienced IgM B cells were rarely found in GCs, indicating that these cells switched rapidly after entering GCs or did not persist in this environment.

Adoptive Transfer↗

PubMed2003

Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation.

The migration of antigen-specific T cells to nonlymphoid tissues is thought to be important for the elimination of foreign antigens from the body. However, recent results showing the migration of activated T cells into many nonlymphoid tissues raised the possibility that antigen-specific T cells do not migrate preferentially to nonlymphoid tissues containing antigen. We addressed this question by tracking antigen-specific CD4 T cells in the whole body after a localized subcutaneous antigen injection. Antigen-specific CD4 T cells proliferated in the skin-draining lymph nodes and the cells that underwent the most cell divisions acquired the ability to bind to CD62P. As time passed, CD62P-binding antigen-specific CD4 T cells with interferon gamma production potential accumulated preferentially at the site of antigen injection but only in recipients that expressed CD62E. Surprisingly, these T cells did not proliferate in the injection site despite showing evidence of more cell divisions than the T cells in the draining lymph nodes. The results suggest that the most divided effector CD4 T cells from the lymph nodes enter the site of antigen deposition via recognition of CD62E on blood vessels and are retained there in a nonproliferative state via recognition of peptide-major histocompatibility complex II molecules.

Adoptive Transfer↗

PubMed2003

Whole-body analysis of T cell responses.

In vivo methods to detect antigen-specific T cell responses at the single-cell level have greatly increased our knowledge of how the immune system works. However, most of these approaches have been confined to analysis of lymphoid tissues. Recently, the development of imaging techniques capable of simultaneously monitoring all the tissues of the body has led to the realization that antigen-experienced T cells reside in non-lymphoid tissues and may play a vital role in protecting the host against pathogens. Therefore, single-cell imaging at the level of the whole organism is needed to fully understand the dynamics of protective immunity.

Animals↗

PubMed2003

Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity.

Peptide:MHC II complexes derived from a fluorescent antigen were detected in vivo to identify the cells that present subcutaneously injected antigen to CD4 T cells. Skin-derived dendritic cells (DCs) that acquired the antigen while in the draining lymph nodes were the first cells to display peptide:MHC II complexes. Presentation by these cells induced CD69, IL-2 production, and maximal proliferation by the T cells. Later, DCs displaying peptide:MHC II complexes migrated from the injection site via a G protein-dependent mechanism. Presentation by these migrants sustained expression of the IL-2 receptor and promoted delayed type hypersensitivity. Therefore, presentation of peptide:MHC II complexes derived from a subcutaneous antigen occurs in two temporally distinct waves with different functional consequences.

Animals↗

PubMed2003

Antigen presentation to naive CD4 T cells in the lymph node.

Although the presentation of peptide-major histocompatibility complex class II (pMHC class II) complexes to CD4 T cells has been studied extensively in vitro, knowledge of this process in vivo is limited. Unlike the in vitro situation, antigen presentation in vivo takes place within a complex microenvironment in which the movements of antigens, antigen-presenting cells (APCs) and T cells are governed by anatomic constraints. Here we review developments in the areas of lymph node architecture, APC subsets and T cell activation that have shed light on how antigen presentation occurs in the lymph nodes.

Animals↗

PubMed2003

Development of a novel transgenic mouse for the study of interactions between CD4 and CD8 T cells during graft rejection.

The goal of this study was the development of a system in which the cooperative interactions between CD4 and CD8 T cells specific for defined peptides from a single minor histocompatibility antigen could be studied. A transgenic mouse strain that expresses chicken ovalbumin (Act-mOVA) on the surface of all cells in the body was produced as a source of tissues containing such an antigen. Skin grafts from Act-mOVA donors were rapidly and completely rejected by wild-type recipients, but only when both CD4 and CD8 T cells were present. CD4 T cells by themselves caused an incomplete form of rejection characterized by rapid but partial contraction of Act-mOVA grafts. CD8 T cells alone caused complete rejection of Act-mOVA skin grafts but only after a long delay. Adoptively transferred ovalbumin-specific TCR-transgenic CD4 and CD8 T cells were stimulated by Act-mOVA graft antigens and CD8 T-cell accumulation in the grafts was enhanced by specific CD4 T cells. These findings, together with the fact that the ligand for ovalbumin peptide-specific CD8 T cells can be detected in Act-mOVA tissues with an MHC-restricted antibody, make this an ideal system for the study of cooperation between CD4 and CD8 T cells.

Adoptive Transfer↗

PubMed2002

In situ analysis reveals physical interactions between CD11b+ dendritic cells and antigen-specific CD4 T cells after subcutaneous injection of antigen.

In situ staining techniques were used to visualize physical interactions between dendritic cell subsets and naive Ag-specific CD4 T cells in the lymph node. Before injection of Ag, CD8(+) dendritic cells and naive OVA-specific CD4 T cells were uniformly distributed throughout the T cell-rich paracortex, whereas CD11b(+) dendritic cells were located mainly in the outer edges of the paracortex near the B cell-rich follicles. Many OVA-specific CD4 T cells were in contact with CD8(+) dendritic cells in the absence of OVA. Within 24 h after s.c. injection of soluble OVA, the OVA-specific CD4 T cells redistributed to the outer paracortex and interacted with CD11b(+), but not CD8(+) dendritic cells. This behavior correlated with the uptake of OVA and the presence of peptide-MHC complexes on the surface of CD11b(+) dendritic cells, and subsequent IL-2 production by the Ag-specific CD4 T cells. These results are consistent with the possibility that CD11b(+) dendritic cells play a central role in the activation of CD4 T cells in response to s.c. Ag.

Animals↗

PubMed2002

Flow cytometric analysis of T cell receptor signal transduction.

Intracellular assays of signal transduction in T cells stimulated by antigen in vivo have been limited by requirements for large numbers of highly purified cells to perform conventional biochemical techniques. Here, we describe a technique using flow cytometry to study signaling events in T cells after antigen recognition in the body.

Adoptive Transfer↗