Alloantibody Production is Regulated by CD4+ T Cells' Alloreactive Pathway, Rather Than Precursor Frequency or Th1/Th2 Differentiation

Abstract

Although CD4+ T cells play an important role in the regulation of allograft rejection, the exact mechanisms by which they operate and the actual contribution of direct and indirect alloreactivity pathways remain to be fully characterized. Previous studies have established a possible relationship between the indirect alloreactivity pathway and antibody production, but interpretation of these results have been complicated by shortcomings inherent to the models used in these studies. To address this issue, we have developed a model based on TCR transgenic mice derived from a CD4 + T-cell clone which recognize specific alloantigens by both alloreactivity pathways. Skin allografts on ab Tcell deficient mice adoptively transferred with transgenic CD4 + T cells were rejected without significant delay between the two alloreactivity pathways. No IgG alloantibody was produced following allograft rejection by the direct alloreactivity pathway alone. Importantly, production of antibodies against alloantigens of the direct pathway was shown to require help from CD4 + T cells activated by the indirect pathway. These results indicate that the events leading to the initiation of immune responses responsible for graft rejection are clearly dependent on the population of antigenpresenting cells involved in T-and B-lymphocyte activation.

Transplant Glomerulopathy May Occur in the Absence of Donor-Specific Antibody and C4d Staining

“…Furthermore, there are extensive animal and initial human data that T cell recognition of processed alloantigen via the indirect pathway is a key factor in initiating and maintaining the progression of chronic allograft rejection (13)(14)(15)(16). In addition, humoral alloimmunity and isotype switching to IgG is dependent on indirect alloreactivity (17,18). Thus, T and B cell involvement may not be two separate or exclusive processes but rather may cooperate with each other.…”

Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells

“…This crossreactivity suggests that, if induced, a humoral response to B6.H-2 bm12 allografts by C57BL/6 recipients would result in autoreactivity. The absence of an Ab response to B6.H-2 bm12 allografts may also be indicative of the absence of T cells activated through the indirect alloantigen presentation pathway, which is proposed to be a major factor initiating alloantigen-specific Ab responses (38,39). Consistent with this, we have been unable to detect an indirect T cell response in C57BL/6 recipients of B6.H-2 bm12 heart or skin allografts to peptides incorporating the 3-aa substitutions of I-A bm12 or by immunizing C57BL/6 mice with the peptides (S. Schenk, unpublished results).…”

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

“…The antigen specificity of the 2.102Tg T cells for I-E p and for Hb(64-76)/I-E k , which can only be recognized through the direct and indirect alloreactive pathway, respectively, has been established in previous studies [8]. In our system, the direct pathway was studied by grafting 2.102Tg mice deficient for RAG-1 (referred to as 2.102Tg RAG -/-) with skin from B10.P (H-2 p ) congenic mice.…”

“…The ELISPOT assay was performed as described previously [8]. Briefly, multiScreen Immobilion-P Filtration plates (Millipore, Bedford, MA, USA) were coated with 4 lg/ml antimouse-IFN-c (R4-6A2; eBioscience, San Diego, CA, USA).…”

“…The purpose of the present work was to characterize alloreactive T cell responses occurring in draining LN (DLN) and in skin allografts, in a murine model of transplantation where both pathways of allorecognition can be independently studied [8]. Whereas the kinetics of rejection were very similar between both pathways, the initiation of the alloreactive responses was definitively different.…”