Alloreactive CD4 T Cell Activation In Vivo: An Autonomous Function of the Indirect Pathway of Alloantigen Presentation

Abstract

Activation of alloreactive CD4 T cells occurs via the direct and indirect pathways of alloantigen presentation. A novel TCR/alloantigen transgenic system was designed that permitted in vivo visualization of CD4 T cell priming through these pathways. When both pathways of alloantigen presentation were intact, CD4 T cell activation in response to cardiac allografts was rapid and systemic by day 4 after transplantation, in contrast to that seen in response to skin allografts, which was delayed until 10–12 days after transplantation. Despite this systemic CD4 T cell activation in response to cardiac allografts, there was a paucity of activated graft-infiltrating CD4 T cells at 4 days posttransplantation. This finding suggests that the initial priming of alloimmune CD4 T cell responses occurs within draining lymphoid organs. Furthermore, alloantigens derived from cardiac allografts failed to promote thymic negative selection of developing thymocytes expressing the alloreactive TCR clonotype. In the absence of a functional direct pathway, the kinetics of activation, anatomic localization, and effector function of alloreactive CD4 T cells remained unchanged. Overall, the present study defines the anatomic and temporal characteristics of CD4 T cell alloimmune responses and demonstrates that CD4 T cell priming via the indirect pathway proceeds optimally in the absence of the direct pathway of alloantigen presentation.

Evidence for Cooperativity in the Rejection of Cardiac Grafts Mediated by CD4+ TCR Tg T Cells Specific for a Defined Allopeptide

“…This same combination of TCR Tg cells and transgenic allografts has also been studied using trachea allografts that demonstrated specific T-cell activation and localization in the trachea allografts, but these did not mediate complete rejection (24). Similarly, rejection required several weeks to develop in adoptive recipients of a hemagglutin-specific CD4+ TCR Tg population (from TS1 mice), into mice with an allograft that expressed the relevant antigen as a transgene (25). Our model also employs a defined protein antigen (K d ) expressed as a transgene but differs from the above models in that the transgene bears the natural MHC class I promoter elements and is thus under physiological control.…”

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

“…Nevertheless, the data reported in this study may rely on a relatively high level of Tg protein expression or unique tissue distribution, and it is not known whether Tg OVA is representative of any natural mHAg. It should be noted that a dominant role for recipient (self) class II MHC in the priming and clonal expansion of mHAg-specific alloreactive CD4 ϩ T cells after cardiac and skin transplantation in mice has also recently been reported (63,64). In one study another Tg protein (in this case hemagglutinin) served as the model mHAg (63).…”

“…It should be noted that a dominant role for recipient (self) class II MHC in the priming and clonal expansion of mHAg-specific alloreactive CD4 ϩ T cells after cardiac and skin transplantation in mice has also recently been reported (63,64). In one study another Tg protein (in this case hemagglutinin) served as the model mHAg (63). In the other, TCR-Tg CD4 ϩ T cell responses against the natural male mHAg H-Y were examined, with results similar to ours (64).…”

Specificity-Based Negative Selection of Autoreactive B Cells during Memory Formation

“…HA104 and HACII mice and the detection of transgenes were described previously (28,29). Both lineages of HA-transgenic mice were backcrossed to BALB/c mice (Harlan, Indianapolis, IN) at least 10 generations before use in these experiments and were maintained in sterile microisolators at the Wistar Institute Animal Facility.…”

“…However, another population, which participates in both primary and memory B cell responses of BALB/c mice, evaded negative selection from the primary B cell repertoire of HA104 mice (26), and memory B cell responses to the PR8 HA were unaffected by tolerance induction (27). In this report, we have analyzed transgenic mice that express PR8 HA as an abundant membrane-bound Ag driven by a MHC class II promoter (HACII mice) (28). In this case too, a population of autoreactive PR8 HA-specific B cells can be activated by primary virus immunization, but unlike HA104 mice, these autoreactive PR8 HA-specific B cells are subjected to negative selection during memory formation in HACII mice.…”